Publications by authors named "Rosa Bacchetta"

81 Publications

Thymic origins of autoimmunity-lessons from inborn errors of immunity.

Semin Immunopathol 2021 Feb 2;43(1):65-83. Epub 2021 Feb 2.

Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Lokey Stem Cell Research Building 265 Campus Drive, West Stanford, CA, 94305, USA.

During their intrathymic development, nascent T cells are empowered to protect against pathogens and to be operative for a life-long acceptance of self. While autoreactive effector T (Teff) cell progenitors are eliminated by clonal deletion, the intrathymic mechanisms by which thymic regulatory T cell (tTreg) progenitors maintain specificity for self-antigens but escape deletion to exert their regulatory functions are less well understood. Both tTreg and Teff development and selection result from finely coordinated interactions between their clonotypic T cell receptors (TCR) and peptide/MHC complexes expressed by antigen-presenting cells, such as thymic epithelial cells and thymic dendritic cells. tTreg function is dependent on expression of the FOXP3 transcription factor, and induction of FOXP3 gene expression by tTreg occurs during their thymic development, particularly within the thymic medulla. While initial expression of FOXP3 is downstream of TCR activation, constitutive expression is fixed by interactions with various transcription factors that are regulated by other extracellular signals like TCR and cytokines, leading to epigenetic modification of the FOXP3 gene. Most of the understanding of the molecular events underlying tTreg generation is based on studies of murine models, whereas gaining similar insight in the human system has been very challenging. In this review, we will elucidate how inborn errors of immunity illuminate the critical non-redundant roles of certain molecules during tTreg development, shedding light on how their abnormal development and function cause well-defined diseases that manifest with autoimmunity alone or are associated with states of immune deficiency and autoinflammation.
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http://dx.doi.org/10.1007/s00281-020-00835-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925499PMC
February 2021

Human-engineered Treg-like cells suppress FOXP3-deficient T cells but preserve adaptive immune responses .

Clin Transl Immunology 2020 25;9(11):e1214. Epub 2020 Nov 25.

Department of Pediatrics Division of Hematology, Oncology Stem Cell Transplantation and Regenerative Medicine Stanford University School of Medicine Stanford CA USA.

Objectives: Genetic or acquired defects in FOXP3 regulatory T cells (Tregs) play a key role in many immune-mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previously, we demonstrated CD4 T cells from healthy donors and IPEX patients can be converted into functional Treg-like cells by lentiviral transfer of (CD4). These CD4 cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical data supporting CD4 cell clinical progression.

Methods: The molecular characterisation of CD4 cells included flow cytometry, qPCR, RNA-seq and TCR-seq. The suppressive function of CD4 cells was assessed in xenograft-versus-host disease (xeno-GvHD) and FOXP3-deficient IPEX-like humanised mouse models. The safety of CD4 cells was evaluated using peripheral blood (PB) humanised (hu)- mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens.

Results: We demonstrate that the conversion of CD4 T cells to CD4 cells leads to specific transcriptional changes as compared to CD4 T-cell transduction in the absence of FOXP3, including upregulation of Treg-related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during cell production. Both allogeneic and autologous CD4 cells protect from xeno-GvHD after two sequential infusions of effector T cells. CD4 cells prevent hyper-proliferation of CD4 memory T cells in the FOXP3-deficient IPEX-like hu-mice. CD4 cells do not impede expansion of antigen-primed T cells or tumor clearance in the PB hu-mice.

Conclusion: These data support the clinical readiness of CD4 cells to treat IPEX syndrome and other immune-mediated diseases caused by insufficient or dysfunctional FOXP3 Tregs.
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http://dx.doi.org/10.1002/cti2.1214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688376PMC
November 2020

Engineered type 1 regulatory T cells designed for clinical use kill primary pediatric acute myeloid leukemia cells.

Haematologica 2020 Sep 28;Online ahead of print. Epub 2020 Sep 28.

Department of Pediatrics, Division of Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford.

Type 1 regulatory (Tr1) T cells induced by enforced expression of IL-10 (LV-10) are being developed as a novel treatment for chemotherapy-resistant myeloid leukemias. In vivo, LV-10 cells do not cause graft vs host disease while mediating graft vs leukemia (GvL) effect against adult acute myeloid leukemia (AML). Since pediatric AML (pAML) and adult AML are different on a genetic and epigenetic level, we investigate herein whether LV-10 cells also efficiently kill pAML cells. We show that the majority of primary pAML are killed by LV-10 cells, with different levels of sensitivity to killing. Transcriptionally, pAML sensitive to LV-10 killing expressed a myeloid maturation signature. Overlaying the signatures of sensitive and resistant pAML onto the public NCI TARGET pAML dataset revealed that sensitive pAML clustered with M5 monocytic pAML and pAML with MLL rearrangement. Resistant pAML clustered with myelomonocytic leukemias and those bearing the core binding factor translocations inv(16) or t(8;21)(RUNX1-RUNX1T1). Furthermore, resistant pAML upregulated the membrane glycoprotein CD200, which binds to the inhibitory receptor CD200R1 on LV-10 cells. To examine if CD200 expression on target cells can impair LV-10 cell function, we overexpressed CD200 in myeloid leukemia cell lines ordinarily sensitive to LV-10 killing. Indeed, LV-10 cells degranulated less and killed fewer CD200-overexpressing cells compared to controls, indicating that pAML can utilize CD200 expression for immune evasion. Altogether, the majority of pAML are killed by LV-10 cells in vitro, supporting further LV-10 cell development as an innovative cell therapy for pAML.
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http://dx.doi.org/10.3324/haematol.2020.263129DOI Listing
September 2020

Human inborn errors of immunity: An expanding universe.

Sci Immunol 2020 07;5(49)

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Molecular, cellular, and clinical studies of human inborn errors of immunity have revolutionized our understanding of their pathogenesis, considerably broadened their spectrum of immunological and clinical phenotypes, and enabled successful targeted therapeutic interventions. These studies have also been of great scientific merit, challenging a number of immunological notions initially established in inbred mice while revealing previously unrecognized mechanisms of host defense by leukocytes and other cells and of both innate and adaptive tolerance to self.
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http://dx.doi.org/10.1126/sciimmunol.abb1662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647049PMC
July 2020

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Front Immunol 2020 21;11:239. Epub 2020 Feb 21.

Department of Pediatrics, Immunology, Allergy, and Retrovirology Baylor College of Medicine, Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, TX, United States.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.
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http://dx.doi.org/10.3389/fimmu.2020.00239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046837PMC
March 2021

Treatment with rapamycin can restore regulatory T-cell function in IPEX patients.

J Allergy Clin Immunol 2020 04 23;145(4):1262-1271.e13. Epub 2019 Dec 23.

San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif. Electronic address:

Background: Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear.

Objective: We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations.

Methods: Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR.

Results: Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor-related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor-related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells.

Conclusions: Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.
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http://dx.doi.org/10.1016/j.jaci.2019.11.043DOI Listing
April 2020

Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome.

Front Immunol 2019 12;10:753. Epub 2019 Apr 12.

Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, United States.

Gain-of-function variants in p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) expressed in lymphocytes, cause activated PI3-kinase δ syndrome (APDS), a primary immunodeficiency that is characterized by recurrent infections, viremia, lymphadenopathy, and autoimmunity. The mechanism of autoimmunity in APDS has not been well-understood. Here, we show the profound skewing of peripheral CD4 T cells to a T follicular helper (T) phenotype in a patient with APDS bearing a novel p110δ variant, Y524S. We also saw a diminishment of transient Foxp3 expression in activated T cells. Mechanistic studies revealed that both the new variant and a previously described, pathogenic variant (E81K) enhanced an interaction between intracellular Osteopontin and p85α. This interaction had been shown in mice to promote T differentiation. Our results demonstrate a new influence of PI3K on human T cell differentiation that is unrelated to its lipid-kinase activity and suggest that T should be monitored in APDS patients.
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http://dx.doi.org/10.3389/fimmu.2019.00753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473200PMC
August 2020

The autoimmune targets in IPEX are dominated by gut epithelial proteins.

J Allergy Clin Immunol 2019 07 23;144(1):327-330.e8. Epub 2019 Apr 23.

Center for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

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http://dx.doi.org/10.1016/j.jaci.2019.02.031DOI Listing
July 2019

The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases.

Immunity 2018 12;49(6):1004-1019

Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, 17176 Stockholm, Sweden.

Thirty years ago, one of the first types of CD4 T regulatory cells was discovered and named T regulatory type 1 (Tr1) cells. Tr1 cells represent a distinct population of T cells, which are induced in the periphery upon antigen exposure under tolerogenic conditions. They produce the immunosuppressive cytokines interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), do not constitutively express FOXP3, and suppress the function of effector immune cells. In this review, the key studies leading to the identification and biological characterization of Tr1 cells are recapitulated. The fundamental role of Tr1 cells in regulating immune responses to pathogenic and non-pathogenic antigens, as well as their use as cell therapeutics, is summarized.
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http://dx.doi.org/10.1016/j.immuni.2018.12.001DOI Listing
December 2018

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency.

J Allergy Clin Immunol 2018 12;142(6):1679-1695

Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford School of Medicine, Stanford, Calif; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, Calif. Electronic address:

Monogenic diseases of the immune system, also known as inborn errors of immunity, are caused by single-gene mutations resulting in immune deficiency and dysregulation. More than 350 diseases have been described to date, and the number is rapidly expanding, with increasing availability of next-generation sequencing facilitating the diagnosis. The spectrum of immune dysregulation is wide, encompassing deficiencies in humoral, cellular, innate, and adaptive immunity; phagocytosis; and the complement system, which lead to autoinflammation and autoimmunity. Multiorgan autoimmunity is a dominant symptom when genetic mutations lead to defects in molecules essential for the development, survival, and/or function of regulatory T (Treg) cells. Studies of "Tregopathies" are providing critical mechanistic information on Treg cell biology, the role of Treg cell-associated molecules, and regulation of peripheral tolerance in human subjects. The pathogenic immune networks underlying these diseases need to be dissected to apply and develop immunomodulatory treatments and design curative treatments using cell and gene therapy. Here we review the pathogenetic mechanisms, clinical presentation, diagnosis, and current and future treatments of major known Tregopathies caused by mutations in FOXP3, CD25, cytotoxic T lymphocyte-associated antigen 4 (CTLA4), LPS-responsive and beige-like anchor protein (LRBA), and BTB domain and CNC homolog 2 (BACH2) and gain-of-function mutations in signal transducer and activator of transcription 3 (STAT3). We also discuss deficiencies in genes encoding STAT5b and IL-10 or IL-10 receptor as potential Tregopathies.
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http://dx.doi.org/10.1016/j.jaci.2018.10.026DOI Listing
December 2018

Epigenetic immune cell counting in human blood samples for immunodiagnostics.

Sci Transl Med 2018 08;10(452)

Ivana Türbachova Laboratory for Epigenetics, Epiontis GmbH, Precision for Medicine Group, 12489 Berlin, Germany.

Immune cell profiles provide valuable diagnostic information for hematologic and immunologic diseases. Although it is the most widely applied analytical approach, flow cytometry is limited to liquid blood. Moreover, either analysis must be performed with fresh samples or cell integrity needs to be guaranteed during storage and transport. We developed epigenetic real-time quantitative polymerase chain reaction (qPCR) assays for analysis of human leukocyte subpopulations. After method establishment, whole blood from 25 healthy donors and 97 HIV patients as well as dried spots from 250 healthy newborns and 24 newborns with primary immunodeficiencies were analyzed. Concordance between flow cytometric and epigenetic data for neutrophils and B, natural killer, CD3 T, CD8 T, CD4 T, and FOXP3 regulatory T cells was evaluated, demonstrating substantial equivalence between epigenetic qPCR analysis and flow cytometry. Epigenetic qPCR achieves both relative and absolute quantifications. Applied to dried blood spots, epigenetic immune cell quantification was shown to identify newborns suffering from various primary immunodeficiencies. Using epigenetic qPCR not only provides a precise means for immune cell counting in fresh-frozen blood but also extends applicability to dried blood spots. This method could expand the ability for screening immune defects and facilitates diagnostics of unobservantly collected samples, for example, in underdeveloped areas, where logistics are major barriers to screening.
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http://dx.doi.org/10.1126/scitranslmed.aan3508DOI Listing
August 2018

Reprogramming human T cell function and specificity with non-viral genome targeting.

Nature 2018 07 11;559(7714):405-409. Epub 2018 Jul 11.

HIV Dynamics and Replication Program, Vector Design and Replication Section, National Cancer Institute, Frederick, MD, USA.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes using recombinant viral vectors, which do not target transgenes to specific genomic sites. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.
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http://dx.doi.org/10.1038/s41586-018-0326-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239417PMC
July 2018

APVO210: A Bispecific Anti-CD86-IL-10 Fusion Protein (ADAPTIR™) to Induce Antigen-Specific T Regulatory Type 1 Cells.

Front Immunol 2018 25;9:881. Epub 2018 May 25.

Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University, Stanford, CA, United States.

IL-10 is a potent immunosuppressive cytokine that promotes the differentiation of tolerogenic dendritic cells (DC-10), and the subsequent induction of antigen-specific T regulatory type 1 (Tr1) cells, which suppress immune responses. However, IL-10 acts on multiple cell types and its effects are not solely inhibitory, therefore, limiting its use as immunomodulant. APVO210 is a bispecific fusion protein composed of an anti-CD86 antibody fused with monomeric IL-10 (ADAPTIR™ from Aptevo Therapeutics). APVO210 specifically induces IL-10R signaling in CD86 antigen-presenting cells, but not in T and B cells. In this study, we tested whether APVO210 promotes the differentiation of tolerogenic DC-10 and the differentiation of antigen-specific CD4 Tr1 cells . We compared the effect of APVO210 with that of recombinant human (rh) IL-10 on the differentiation of DC-10, induction of alloantigen-specific anergic CD4 T cells, enrichment in CD49bLAG3 Tr1 cells mediating antigen-specific suppression, and stability upon exposure to inflammatory cytokines. APVO210 induced the differentiation of tolerogenic DC (DC-A210) that produced high levels of IL-10, expressed CD86, HLA-G, and intermediate levels of CD14 and CD16. These DC-A210 induced alloantigen-specific anergic T-cell cultures (T-alloA210) that were enriched in CD49b LAG3 Tr1 cells, produced high levels of IL-10, and had suppressive properties. The phenotype and high IL-10 production by DC-A210, and the alloantigen-specific anergy of T-alloA210 were preserved upon exposure to the inflammatory cytokines IL-1β, IL-6, and TNF-α. The effects of APVO210 were comparable to that of dimeric rh IL-10. In conclusion, our data demonstrate that APVO210 drives the differentiation of tolerogenic DC and functional alloantigen-specific Tr1 cells . Since APVO210 specifically targets CD86 cells, we hypothesize that it will specifically target CD86 DC to induce Tr1 cells , and mediate antigen-specific immunological tolerance by induction of tolerogenic DC and Tr1 cells.
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http://dx.doi.org/10.3389/fimmu.2018.00881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980965PMC
July 2019

Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis.

J Allergy Clin Immunol 2018 12 27;142(6):1909-1921.e9. Epub 2018 Apr 27.

San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy; Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, Calif. Electronic address:

Background: Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a fatal autoimmune syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed.

Objective: We sought to evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with IPEX syndrome immune pathology.

Methods: We developed a model of humanized mice (huMice) in which the human hematopoietic system is stably knocked down or knocked out for the FOXP3 gene (knockdown [KD]/knockout [KO] huMice).

Results: Because FOXP3-KD/KO was not 100% effective, residual FOXP3 expression in hematopoietic stem progenitor cells was sufficient to give rise to Treg cells with normal expression of FOXP3. However, numerous defects appeared in the Teff cell compartment. Compared with control mice, FOXP3-KD/KO huMice showed altered thymocyte differentiation, with KD/KO thymocytes displaying significantly reduced T-cell receptor (TCR) signaling strength and increased TCR repertoire diversity. Peripheral KD/KO Teff cells were expanded and showed signs of homeostatic proliferation, such as a significantly contracted TCR repertoire, a severely reduced naive compartment, decreased telomeric repeat-binding factor 2 expression, and a skew toward a T2 profile, resembling an aged immune system. Consistent with results in FOXP3-KD/KO huMice, analysis of patients with IPEX syndrome provided evidence of defects in the Teff cell compartment at both the thymic and peripheral levels.

Conclusions: These findings support an intrinsic role for human FOXP3 in controlling thymocyte maturation and peripheral expansion of Teff cells and reveal a previously undescribed pathogenic mechanism through an altered Teff cell compartment in patients with IPEX syndrome.
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http://dx.doi.org/10.1016/j.jaci.2018.03.015DOI Listing
December 2018

Neutralizing Anti-Cytokine Autoantibodies Against Interferon-α in Immunodysregulation Polyendocrinopathy Enteropathy X-Linked.

Front Immunol 2018 29;9:544. Epub 2018 Mar 29.

Department of Pediatric Stem Cell Transplantation and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, United States.

Anti-cytokine autoantibodies (ACAAs) have been described in a growing number of primary immunodeficiencies with autoimmune features, including autoimmune polyendocrine syndrome type I (APS-1), a prototypical disease of defective T cell-mediated central tolerance. Whether defects in peripheral tolerance lead to similar ACAAs is unknown. Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) is caused by mutations in , a master regulator of T regulatory cells (T), and consequently results in defective T cell-mediated peripheral tolerance. Unique autoantibodies have previously been described in IPEX. To test the hypothesis that ACAAs are present in IPEX, we designed and fabricated antigen microarrays. We discovered elevated levels of IgG ACAAs against interferon-α (IFN-α) in a cohort of IPEX patients. Serum from IPEX patients blocked IFN-α signaling and blocking activity was tightly correlated with ACAA titer. To show that blocking activity was mediated by IgG and not other serum factors, we purified IgG and showed that blocking activity was contained entirely in the immunoglobulin fraction. We also screened for ACAAs against IFN-α in a second geographically distinct cohort. In these samples, ACAAs against IFN-α were elevated in a analysis. In summary, we report the discovery of ACAAs against IFN-α in IPEX, an experiment of nature demonstrating the important role of peripheral T cell tolerance.
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http://dx.doi.org/10.3389/fimmu.2018.00544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885158PMC
May 2019

Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization.

Front Immunol 2017 15;8:1844. Epub 2018 Jan 15.

Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboudumc, Nijmegen, Netherlands.

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.
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http://dx.doi.org/10.3389/fimmu.2017.01844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775516PMC
January 2018

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study.

J Allergy Clin Immunol 2018 03 11;141(3):1036-1049.e5. Epub 2017 Dec 11.

Department of Pediatric Hematology and Oncology, Baylor College of Medicine Texas Children's Hospital, Houston, Tex.

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.

Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.

Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.

Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.

Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.
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http://dx.doi.org/10.1016/j.jaci.2017.10.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050203PMC
March 2018

Identity and Diversity of Human Peripheral Th and T Regulatory Cells Defined by Single-Cell Mass Cytometry.

J Immunol 2018 01 27;200(1):336-346. Epub 2017 Nov 27.

Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA 94305;

Human CD3CD4 Th cells, FOXP3 T regulatory (Treg) cells, and T regulatory type 1 (Tr1) cells are essential for ensuring peripheral immune response and tolerance, but the diversity of Th, Treg, and Tr1 cell subsets has not been fully characterized. Independent functional characterization of human Th1, Th2, Th17, T follicular helper (Tfh), Treg, and Tr1 cells has helped to define unique surface molecules, transcription factors, and signaling profiles for each subset. However, the adequacy of these markers to recapitulate the whole CD3CD4 T cell compartment remains questionable. In this study, we examined CD3CD4 T cell populations by single-cell mass cytometry. We characterize the CD3CD4 Th, Treg, and Tr1 cell populations simultaneously across 23 memory T cell-associated surface and intracellular molecules. High-dimensional analysis identified several new subsets, in addition to the already defined CD3CD4 Th, Treg, and Tr1 cell populations, for a total of 11 Th cell, 4 Treg, and 1 Tr1 cell subsets. Some of these subsets share markers previously thought to be selective for Treg, Th1, Th2, Th17, and Tfh cells, including CD194 (CCR4)FOXP3 Treg and CD183 (CXCR3)T-bet Th17 cell subsets. Unsupervised clustering displayed a phenotypic organization of CD3CD4 T cells that confirmed their diversity but showed interrelation between the different subsets, including similarity between Th1-Th2-Tfh cell populations and Th17 cells, as well as similarity of Th2 cells with Treg cells. In conclusion, the use of single-cell mass cytometry provides a systems-level characterization of CD3CD4 T cells in healthy human blood, which represents an important baseline reference to investigate abnormalities of different subsets in immune-mediated pathologies.
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http://dx.doi.org/10.4049/jimmunol.1701025DOI Listing
January 2018

Forkhead-Box-P3 Gene Transfer in Human CD4 T Conventional Cells for the Generation of Stable and Efficient Regulatory T Cells, Suitable for Immune Modulatory Therapy.

Front Immunol 2017 12;8:1282. Epub 2017 Oct 12.

Department of Stem Cell Transplantation and Regenerative Medicine, Division of Pediatrics, Stanford School of Medicine, Stanford, CA, United States.

The development of novel approaches to control immune responses to self- and allogenic tissues/organs represents an ambitious goal for the management of autoimmune diseases and in transplantation. Regulatory T cells (Tregs) are recognized as key players in the maintenance of peripheral tolerance in physiological and pathological conditions, and Treg-based cell therapies to restore tolerance in T cell-mediated disorders have been designed. However, several hurdles, including insufficient number of Tregs, their stability, and their antigen specificity, have challenged Tregs clinical applicability. In the past decade, the ability to engineer T cells has proven a powerful tool to redirect specificity and function of different cell types for specific therapeutic purposes. By using lentivirus-mediated gene transfer of the thymic-derived Treg transcription factor forkhead-box-P3 (FOXP3) in conventional CD4 T cells, we converted effector T cells into Treg-like cells, endowed with potent and suppressive activity. The resulting CD4 T-cell population displays stable phenotype and suppressive function. We showed that this strategy restores Treg function in T lymphocytes from patients carrying mutations in [immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)], in whom CD4 T cell could be used as therapeutics to control autoimmunity. Here, we will discuss the potential advantages of using CD4 T cells for application in inflammatory diseases, where tissue inflammation may undermine the function of natural Tregs. These findings pave the way for the use of engineered Tregs not only in IPEX syndrome but also in autoimmune disorders of different origin and in the context of stem cell and organ transplantation.
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http://dx.doi.org/10.3389/fimmu.2017.01282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643480PMC
October 2017

Severe Toxoplasma gondii infection in a member of a NFKB2-deficient family with T and B cell dysfunction.

Clin Immunol 2017 10 14;183:273-277. Epub 2017 Sep 14.

University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.clim.2017.09.011DOI Listing
October 2017

Peanut-specific type 1 regulatory T cells induced in vitro from allergic subjects are functionally impaired.

J Allergy Clin Immunol 2018 01 6;141(1):202-213.e8. Epub 2017 Jul 6.

Division of Stem Cell Transplantation and Regenerative Medicine at Stanford University, and Department of Pediatrics, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, Calif. Electronic address:

Background: Peanut allergy (PA) is a life-threatening condition that lacks regulator-approved treatment. Regulatory T type 1 (T1) cells are potent suppressors of immune responses and can be induced in vivo upon repeated antigen exposure or in vitro by using tolerogenic dendritic cells. Whether oral immunotherapy (OIT) leads to antigen-specific T1 cell induction has not been established.

Objectives: We sought to determine whether peanut-specific T1 cells can be generated in vitro from peripheral blood of patients with PA at baseline or during OIT and whether they are functional compared with peanut-specific T1 cells induced from healthy control (HC) subjects.

Methods: Tolerogenic dendritic cells were differentiated in the presence of IL-10 from PBMCs of patients with PA and HC subjects pulsed with the main peanut allergens of Arachis hypogaea, Ara h 1 and 2, and used as antigen-presenting cells for autologous CD4 T cells (CD4 T cells coincubated with tolerogenic dendritic cells pulsed with the main peanut allergens [pea-T10 cells]). Pea-T10 cells were characterized by the presence of CD49b lymphocyte-activation gene 3 (LAG3) T1 cells, antigen-specific proliferative responses, and cytokine production.

Results: CD49bLAG3 T1 cells were induced in pea-T10 cells at comparable percentages from HC subjects and patients with PA. Despite their antigen specificity, pea-T10 cells of patients with PA with or without OIT, as compared with those of HC subjects, were not anergic and had high T2 cytokine production upon peanut-specific restimulation.

Conclusions: Peanut-specific T1 cells can be induced from HC subjects and patients with PA, but those from patients with PA are functionally defective independent of OIT. The unfavorable T1/T2 ratio is discussed as a possible cause of PA T1 cell impairment.
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http://dx.doi.org/10.1016/j.jaci.2017.05.045DOI Listing
January 2018

From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation.

Ann N Y Acad Sci 2018 04 25;1417(1):5-22. Epub 2016 Feb 25.

Department of Pediatrics, Division of Pediatric Stem Cells, Transplantation and Regenerative Medicine, Stanford University Medical School, Stanford, California.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder that increasingly has gained attention as a model of genetic autoimmunity. Numerous papers documenting the key clinical and molecular characteristics of IPEX have provided a detailed understanding of this devastating disease. IPEX is a primary immunodeficiency caused by mutations in the gene FOXP3, which encodes an essential transcription factor required for maintenance of thymus-derived regulatory T (tT ) cells. tT  cell dysfunction is the main pathogenic event leading to multiorgan autoimmunity in IPEX. In addition to the traditional clinical presentation (i.e., severe enteropathy, type 1 diabetes, and eczema), IPEX may encompass other variable and distinct clinical manifestations. As IPEX awareness and characterization have increased, so has identification of FOXP3 mutations, with at least 70 to date. Thus, while FOXP3 is the unifying gene, IPEX is a complex and diverse clinical continuum of disorders. Despite understanding IPEX pathogenesis, new treatment options have remained elusive, although early diagnosis led to hematopoietic stem cell transplantation (HSCT) and immunosuppression treatment and improved patient outcomes. Here, we review current knowledge about IPEX syndrome and highlight findings that could lead to novel targeted treatments.
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http://dx.doi.org/10.1111/nyas.13011DOI Listing
April 2018

Hurdles in therapy with regulatory T cells.

Sci Transl Med 2015 Sep;7(304):304ps18

AG Transplantationstoleranz, Charite Universitätsmedizin, Institut für Med. Imunologie, Augustenburgerplatz 1, 13353 Berlin, Germany.

Improper activation of the immune system contributes to a variety of clinical conditions, including autoimmune and allergic diseases as well as solid organ and bone marrow transplantation. One approach to counteract this activation is through adoptive therapy with regulatory T cells (Tregs). Efforts to manufacture these cells have led to good maunfacturing practice-compliant protocols, and Treg products are entering early clinical trials. Here, we report the stance of the European Union Cooperation in Science and Technology Action BM1305, "Action to Focus and Accelerate Cell-based Tolerance-inducing Therapies-A FACTT," which identifies hurdles hindering Treg clinical applications in Europe and provides possible solutions.
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http://dx.doi.org/10.1126/scitranslmed.aaa7721DOI Listing
September 2015

Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells.

Nat Biotechnol 2015 Sep 29;33(9):985-989. Epub 2015 Jun 29.

Department of Pediatrics, Stanford University, Stanford, California, USA.

CRISPR-Cas-mediated genome editing relies on guide RNAs that direct site-specific DNA cleavage facilitated by the Cas endonuclease. Here we report that chemical alterations to synthesized single guide RNAs (sgRNAs) enhance genome editing efficiency in human primary T cells and CD34(+) hematopoietic stem and progenitor cells. Co-delivering chemically modified sgRNAs with Cas9 mRNA or protein is an efficient RNA- or ribonucleoprotein (RNP)-based delivery method for the CRISPR-Cas system, without the toxicity associated with DNA delivery. This approach is a simple and effective way to streamline the development of genome editing with the potential to accelerate a wide array of biotechnological and therapeutic applications of the CRISPR-Cas technology.
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http://dx.doi.org/10.1038/nbt.3290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729442PMC
September 2015

Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3.

Blood 2015 Jun 1;125(25):3886-95. Epub 2015 Apr 1.

Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA; Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA.

Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific "humanized" mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics.
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http://dx.doi.org/10.1182/blood-2014-12-618363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473116PMC
June 2015

Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies.

Nat Rev Gastroenterol Hepatol 2015 May 17;12(5):293-302. Epub 2015 Mar 17.

Division of Pediatric Gastroenterology, Hepatology and Nutrition, University Paris Descartes Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France.

Congenital diarrhoeal disorders (CDDs) represent an evolving web of rare chronic enteropathies, with a typical onset early in life. In many of these conditions, severe chronic diarrhoea represents the primary clinical manifestation, whereas in others diarrhoea is only a component of a more complex multi-organ or systemic disorder. Typically, within the first days of life, diarrhoea leads to a life-threatening condition highlighted by severe dehydration and serum electrolyte abnormalities. Thus, in the vast majority of cases appropriate therapy must be started immediately to prevent dehydration and long-term, sometimes severe, complications. The number of well-characterized disorders attributed to CDDs has gradually increased over the past several years, and many new genes have been identified and functionally related to CDDs, opening new diagnostic and therapeutic perspectives. Molecular analysis has changed the diagnostic scenario in CDDs, and led to a reduction in invasive and expensive procedures. Major advances have been made in terms of pathogenesis, enabling a better understanding not only of these rare conditions but also of more common diseases mechanisms.
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http://dx.doi.org/10.1038/nrgastro.2015.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599016PMC
May 2015

Gene/cell therapy approaches for Immune Dysregulation Polyendocrinopathy Enteropathy X-linked syndrome.

Curr Gene Ther 2014 ;14(6):422-8

San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20131, Milan, Italy.

Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare autoimmune disease due to mutations in the gene encoding for Forkhead box P3 (FOXP3), a transcription factor fundamental for the function of thymus-derived (t) regulatory T (Treg) cells. The dysfunction of Treg cells results in the development of devastating autoimmune manifestations affecting multiple organs, eventually leading to premature death in infants, if not promptly treated by hematopoietic stem cell transplantation (HSCT). Novel gene therapy strategies can be developed for IPEX syndrome as more definitive cure than allogeneic HSCT. Here we describe the therapeutic approaches, alternative to HSCT, currently under development. We described that effector T cells can be converted in regulatory T cells by LV-mediated FOXP3-gene transfer in differentiated T lymphocytes. Despite FOXP3 mutations mainly affect a highly specific T cell subset, manipulation of stem cells could be required for long-term remission of the disease. Therefore, we believe that a more comprehensive strategy should aim at correcting FOXP3-mutated stem cells. Potentials and hurdles of both strategies will be highlighted here.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443799PMC
http://dx.doi.org/10.2174/1566523214666141001123828DOI Listing
July 2015

BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related SCT.

Bone Marrow Transplant 2014 Nov 11;49(11):1400-1404. Epub 2014 Aug 11.

San Raffaele Telethon Institute for Gene Therapy (HSRTIGET), Division of Regenerative Medicine, Stem Cells, and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.

The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic SCT (allo-HSCT). We applied whole-genome analysis to investigate genetic variants-other than HLA class I and II-associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single-nucleotide polymorphisms (SNPs) in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong linkage disequilibrium between each other (R(2)=0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P<0.00001 for BAT2 SNP rs11538264, and P<0.0001 for BAT3 SNP rs10484558), whereas the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs 2.6%, nominal P=1.15 × 10(-8); and adjusted P=0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent a novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT.
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http://dx.doi.org/10.1038/bmt.2014.177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222814PMC
November 2014

Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications.

Curr Top Microbiol Immunol 2014 ;380:39-68

San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy,

T regulatory Type 1 (Tr1) cells are adaptive T regulatory cells characterized by the ability to secrete high levels of IL-10 and minimal amounts of IL-4 and IL-17. Recently, CD49b and LAG-3 have been identified as Tr1-cell-specific biomarkers in mice and humans. Tr1 cells suppress T-cell- and antigen-presenting cell- (APC) responses primarily via the secretion of IL-10 and TGF-β. In addition, Tr1 cells release granzyme B and perforin and kill myeloid cells. Tr1 cells inhibit T cell responses also via cell-contact dependent mechanisms mediated by CTLA-4 or PD-1, and by disrupting the metabolic state of T effector cells via the production of the ectoenzymes CD39 and CD73. Tr1 cells were first described in peripheral blood of patients who developed tolerance after HLA-mismatched fetal liver hematopoietic stem cell transplant. Since their discovery, Tr1 cells have been proven to be important in maintaining immunological homeostasis and preventing T-cell-mediated diseases. Furthermore, the possibility to generate and expand Tr1 cells in vitro has led to their utilization as cellular therapy in humans. In this chapter we summarize the unique and distinctive biological properties of Tr1 cells, the well-known and newly discovered Tr1-cell biomarkers, and the different methods to induce Tr1 cells in vitro and in vivo. We also address the role of Tr1 cells in infectious diseases, autoimmunity, and transplant rejection in different pre-clinical disease models and in patients. Finally, we highlight the pathological settings in which Tr1 cells can be beneficial to prevent or to cure the disease.
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http://dx.doi.org/10.1007/978-3-662-43492-5_3DOI Listing
November 2014