Publications by authors named "Peter A Savage"

23 Publications

  • Page 1 of 1

A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells.

Cell 2021 Jul 21;184(15):3981-3997.e22. Epub 2021 Jun 21.

Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA. Electronic address:

A fraction of mature T cells can be activated by peripheral self-antigens, potentially eliciting host autoimmunity. We investigated homeostatic control of self-activated T cells within unperturbed tissue environments by combining high-resolution multiplexed and volumetric imaging with computational modeling. In lymph nodes, self-activated T cells produced interleukin (IL)-2, which enhanced local regulatory T cell (Treg) proliferation and inhibitory functionality. The resulting micro-domains reciprocally constrained inputs required for damaging effector responses, including CD28 co-stimulation and IL-2 signaling, constituting a negative feedback circuit. Due to these local constraints, self-activated T cells underwent transient clonal expansion, followed by rapid death ("pruning"). Computational simulations and experimental manipulations revealed the feedback machinery's quantitative limits: modest reductions in Treg micro-domain density or functionality produced non-linear breakdowns in control, enabling self-activated T cells to subvert pruning. This fine-tuned, paracrine feedback process not only enforces immune homeostasis but also establishes a sharp boundary between autoimmune and host-protective T cell responses.
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http://dx.doi.org/10.1016/j.cell.2021.05.028DOI Listing
July 2021

Altered selection on a single self-ligand promotes susceptibility to organ-specific T cell infiltration.

J Exp Med 2021 Jun;218(6)

Department of Pathology, University of Chicago, Chicago, IL.

For the large array of self-peptide/MHC class II (pMHC-II) complexes displayed in the body, it is unclear whether CD4+ T cell tolerance must be imparted for each individual complex or whether pMHC-II-nonspecific bystander mechanisms are sufficient to confer tolerance by acting broadly on T cells reactive to multiple self-pMHC-II ligands. Here, via reconstitution of T cell-deficient mice, we demonstrate that altered T cell selection on a single prostate-specific self-pMHC-II ligand renders recipient mice susceptible to prostate-specific T cell infiltration. Mechanistically, this self-pMHC-II complex is required for directing antigen-specific cells into the Foxp3+ regulatory T cell lineage but does not induce clonal deletion to a measurable extent. Thus, our data demonstrate that polyclonal T reg cells are unable to functionally compensate for a breach in tolerance to a single self-pMHC-II complex in this setting, revealing vulnerabilities in antigen-nonspecific bystander mechanisms of immune tolerance.
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http://dx.doi.org/10.1084/jem.20200701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091134PMC
June 2021

Eomes identifies thymic precursors of self-specific memory-phenotype CD8 T cells.

Nat Immunol 2020 05 13;21(5):567-577. Epub 2020 Apr 13.

Department of Pathology, University of Chicago, Chicago, IL, USA.

Unprimed mice harbor a substantial population of 'memory-phenotype' CD8 T cells (CD8-MP cells) that exhibit hallmarks of activation and innate-like functional properties. Due to the lack of faithful markers to distinguish CD8-MP cells from bona fide CD8 memory T cells, the developmental origins and antigen specificities of CD8-MP cells remain incompletely defined. Using deep T cell antigen receptor (TCR) sequencing, we found that the TCRs expressed by CD8-MP cells are highly recurrent and distinct from the TCRs expressed by naive-phenotype CD8 T cells. CD8-MP clones exhibited reactivity to widely expressed self-ligands. T cell precursors expressing CD8-MP TCRs showed upregulation of the transcription factor Eomes during maturation in the thymus, prior to induction of the full memory phenotype, which is suggestive of a unique program triggered by recognition of self-ligands. Moreover, CD8-MP cells infiltrate oncogene-driven prostate tumors and express high densities of PD-1, which suggests potential roles in antitumor immunity and the response to immunotherapy.
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http://dx.doi.org/10.1038/s41590-020-0653-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193531PMC
May 2020

Regulatory T Cell Development.

Annu Rev Immunol 2020 04 28;38:421-453. Epub 2020 Jan 28.

Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA; email:

Foxp3-expressing CD4 regulatory T (Treg) cells play key roles in the prevention of autoimmunity and the maintenance of immune homeostasis and represent a major barrier to the induction of robust antitumor immune responses. Thus, a clear understanding of the mechanisms coordinating Treg cell differentiation is crucial for understanding numerous facets of health and disease and for developing approaches to modulate Treg cells for clinical benefit. Here, we discuss current knowledge of the signals that coordinate Treg cell development, the antigen-presenting cell types that direct Treg cell selection, and the nature of endogenous Treg cell ligands, focusing on evidence from studies in mice. We also highlight recent advances in this area and identify key unanswered questions.
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http://dx.doi.org/10.1146/annurev-immunol-100219-020937DOI Listing
April 2020

Immune profiles in primary squamous cell carcinoma of the head and neck.

Oral Oncol 2019 09 12;96:77-88. Epub 2019 Jul 12.

Department of Medicine, University of Chicago, IL, United States. Electronic address:

Objectives: In this study we describe the tumor microenvironment, the signaling pathways and genetic alterations associated with the presence or absence of CD8+ T-cell infiltration in primary squamous cell carcinoma of the head and neck (SCCHN) tumors.

Materials And Methods: Two SCCHN multi-analyte cohorts were utilized, the Cancer Genome Atlas (TCGA) and the Chicago Head and Neck Genomics (CHGC) cohort. A well-established chemokine signature classified SCCHN tumors into high and low CD8+ T-cell inflamed phenotypes (TCIP-H, TCIP-L respectively). Gene set enrichment and iPANDA analyses were conducted to dissect differences in signaling pathways, somatic mutations and copy number aberrations for TCIP-H versus TCIP-L tumors, stratified by HPV status.

Results: TCIP-H SCCHN tumors were enriched in multiple immune checkpoints irrespective of HPV-status. HPV-positive tumors were enriched in markers of T-regulatory cells (Tregs) and HPV-negative tumors in protumorigenic M2 macrophages. TCIP-L SCCHN tumors were enriched for the β-catenin/WNT and Hedgehog signaling pathways, had frequent mutations in NSD1, amplifications in EGFR and YAP1, as well as CDKN2A deletions. TCIP-H SCCHN tumors were associated with the MAPK/ERK, JAK/STAT and mTOR/AKT signaling pathways, and were enriched in CASP8, EP300, EPHA2, HRAS mutations, CD274, PDCD1LG2, JAK2 amplifications.

Conclusions: Our findings support that combinatorial immune checkpoint blockade and depletion strategies targeting Tregs in HPV-positive and M2 macrophages in HPV-negative tumors may lead to improved antitumor immune responses in patients with TCIP-H SCCHN. We highlight novel pathways and genetic events that may serve as candidate biomarkers and novel targeted therapies to enhance the efficacy of immunotherapy in SCCHN patients.
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http://dx.doi.org/10.1016/j.oraloncology.2019.06.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893610PMC
September 2019

Negligible Role for Deletion Mediated by cDC1 in CD8 T Cell Tolerance.

J Immunol 2019 05 22;202(9):2628-2635. Epub 2019 Mar 22.

Committee on Immunology, University of Chicago, Chicago, IL 60637;

Deletion of CD8 T cells by dendritic cells (DCs) is recognized as a critical mechanism of immune tolerance to self-antigens. Although DC-mediated peripheral deletion of autoreactive CD8 T cells has been demonstrated using T cells reactive to model Ags, its role in shaping the naturally occurring polyclonal CD8 T cell repertoire has not been defined. Using mice lacking cross-presenting CD8α and CD103 DCs (also known as type 1 conventional [cDC1]), we demonstrate that peripheral deletion of CD8 T cells reactive to a model tissue Ag is dependent on cDC1. However, endogenous CD8 T cells from the periphery of mice do not exhibit heightened self-reactivity, and deep TCR sequencing of CD8 T cells from and mice reveals that cDC1 have a minimal impact on shaping the peripheral CD8 T cell repertoire. Thus, although evident in reductionist systems, deletion of polyclonal self-specific CD8 T cells by cDC1 plays a negligible role in enforcing tolerance to natural self-ligands.
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http://dx.doi.org/10.4049/jimmunol.1801621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478510PMC
May 2019

Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability.

J Clin Invest 2019 02 22;129(2):902-914. Epub 2019 Jan 22.

Department of Pathology, The University of Chicago, Chicago, Illinois, USA.

Graft-versus-host disease (GVHD) is a complication of hematopoietic stem cell transplantation (HSCT) that affects multiple organs. GVHD-associated intestinal damage can be separated into two distinct phases, initiation and propagation, which correspond to conditioning-induced damage and effector T cell activation and infiltration, respectively. Substantial evidence indicates that intestinal damage induced by pretransplant conditioning is a key driver of GVHD initiation. Here, we aimed to determine the impact of dysregulated intestinal permeability on the subsequent GVHD propagation phase. The initiation phase of GVHD was unchanged in mice lacking long MLCK (MLCK210), an established regulator of epithelial tight junction permeability. However, MLCK210-deficient mice were protected from sustained barrier loss and exhibited limited GVHD propagation, as indicated by reduced histopathology, fewer CD8+ effector T cells in the gut, and improved overall survival. Consistent with these findings, intestinal epithelial MLCK210 expression and enzymatic activity were similarly increased in human and mouse GVHD biopsies. Intestinal epithelial barrier loss mediated by MLCK210 is therefore a key driver of the GVHD propagation. These data suggest that inhibition of MLCK210-dependent barrier regulation may be an effective approach to limiting GVHD progression.
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http://dx.doi.org/10.1172/JCI98554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355225PMC
February 2019

Unlocking the Complexities of Tumor-Associated Regulatory T Cells.

J Immunol 2018 01;200(2):415-421

Department of Pathology, University of Chicago, Chicago, IL 60637

Regulatory T (Treg) cells are found at elevated densities in many human cancers and are thought to be a major barrier to the generation of robust antitumor T cell responses. In this review, we discuss recent advances in the understanding of tumor-associated Treg cell diversity and function. Emerging evidence indicates that the transcriptional program of Treg cells infiltrating human cancers may represent a composite program blending a tissue-associated expression signature with an additional tumor-specific signature common to Treg cells from multiple cancer types. Studies in mouse models have defined unique molecular pathways required for Treg cell function in the tumor context that can be manipulated to selectively dampen intratumoral Treg cell activity. Finally, an expanding body of work has revealed diverse functions for Treg cells in nonlymphoid tissues that are unrelated to immune suppression, suggesting a need to explore functions of intratumoral Treg cells beyond the regulation of antitumor immunity.
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http://dx.doi.org/10.4049/jimmunol.1701188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763514PMC
January 2018

Identification of Natural Regulatory T Cell Epitopes Reveals Convergence on a Dominant Autoantigen.

Immunity 2017 07 11;47(1):107-117.e8. Epub 2017 Jul 11.

Department of Pathology, University of Chicago, Chicago, IL 60637, USA. Electronic address:

Regulatory T (Treg) cells expressing the transcription factor Foxp3 are critical for the prevention of autoimmunity and the suppression of anti-tumor immunity. The major self-antigens recognized by Treg cells remain undefined, representing a substantial barrier to the understanding of immune regulation. Here, we have identified natural Treg cell ligands in mice. We found that two recurrent Treg cell clones, one prevalent in prostate tumors and the other associated with prostatic autoimmune lesions, recognized distinct non-overlapping MHC-class-II-restricted peptides derived from the same prostate-specific protein. Notably, this protein is frequently targeted by autoantibodies in experimental models of prostatic autoimmunity. On the basis of these findings, we propose a model in which Treg cell responses at peripheral sites converge on those self-proteins that are most susceptible to autoimmune attack, and we suggest that this link could be exploited as a generalizable strategy for identifying the Treg cell antigens relevant to human autoimmunity.
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http://dx.doi.org/10.1016/j.immuni.2017.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562039PMC
July 2017

Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage.

Immunity 2016 05 26;44(5):1102-13. Epub 2016 Apr 26.

Department of Pathology, University of Chicago, Chicago, IL 60637, USA. Electronic address:

The promiscuous expression of tissue-restricted antigens in the thymus, driven in part by autoimmune regulator (Aire), is critical for the protection of peripheral tissues from autoimmune attack. Aire-dependent processes are thought to promote both clonal deletion and the development of Foxp3(+) regulatory T (Treg) cells, suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechanisms. Here, examination of autoimmune lesions in Aire(-/-) mice revealed an unexpected third possibility. We found that the predominant conventional T cell clonotypes infiltrating target lesions express antigen receptors that were preferentially expressed by Foxp3(+) Treg cells in Aire(+/+) mice. Thus, Aire enforces immune tolerance by ensuring that distinct autoreactive T cell specificities differentiate into the Treg cell lineage; dysregulation of this process results in the diversion of Treg cell-biased clonotypes into pathogenic conventional T cells.
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http://dx.doi.org/10.1016/j.immuni.2016.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871732PMC
May 2016

Dendritic Cells Coordinate the Development and Homeostasis of Organ-Specific Regulatory T Cells.

Immunity 2016 Apr 29;44(4):847-59. Epub 2016 Mar 29.

Department of Pathology, University of Chicago, Chicago, IL 60637, USA. Electronic address:

Although antigen recognition mediated by the T cell receptor (TCR) influences many facets of Foxp3(+) regulatory T (Treg) cell biology, including development and function, the cell types that present antigen to Treg cells in vivo remain largely undefined. By tracking a clonal population of Aire-dependent, prostate-specific Treg cells in mice, we demonstrated an essential role for dendritic cells (DCs) in regulating organ-specific Treg cell biology. We have shown that the thymic development of prostate-specific Treg cells required antigen presentation by DCs. Moreover, Batf3-dependent CD8α(+) DCs were dispensable for the development of this clonotype and had negligible impact on the polyclonal Treg cell repertoire. In the periphery, CCR7-dependent migratory DCs coordinated the activation of organ-specific Treg cells in the prostate-draining lymph nodes. Our results demonstrate that the development and peripheral regulation of organ-specific Treg cells are dependent on antigen presentation by DCs, implicating DCs as key mediators of organ-specific immune tolerance.
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http://dx.doi.org/10.1016/j.immuni.2016.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842258PMC
April 2016

Close Encounters of the Tertiary Kind.

Immunity 2015 Sep;43(3):418-20

Department of Pathology, University of Chicago, Chicago, IL 60637, USA. Electronic address:

Elucidating the function of tumor-infiltrating regulatory T (Treg) cells has been difficult. In this issue of Immunity, Joshi et al. (2015) demonstrate that Treg cells associated with murine lung cancers are found within tertiary lymphoid structures and actively restrain effector T cells at the tumor site.
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http://dx.doi.org/10.1016/j.immuni.2015.08.022DOI Listing
September 2015

Ablation of B7-H3 but Not B7-H4 Results in Highly Increased Tumor Burden in a Murine Model of Spontaneous Prostate Cancer.

Cancer Immunol Res 2015 Aug 29;3(8):849-54. Epub 2015 Jun 29.

Program in Immunology, Howard Hughes Medical Institute, and Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The costimulatory molecules B7-H3 and B7-H4 are overexpressed in a variety of human tumors and have been hypothesized as possible biomarkers and immunotherapeutic targets. Despite this potential, the predominating uncertainty about their functional implication in tumor-host interaction hampers their evaluation as a target for cancer therapy. By means of a highly physiologic, spontaneous tumor model in mice, we establish a causal link between B7-H3 and host tumor control and found B7-H4 to be redundant.
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http://dx.doi.org/10.1158/2326-6066.CIR-15-0100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939565PMC
August 2015

Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease.

Sci Transl Med 2014 Jul;6(243):243ra87

Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.

Previous studies have shown a correlation between pretransplant conditioning intensity, intestinal barrier loss, and graft-versus-host disease (GVHD) severity. However, because irradiation and other forms of pretransplant conditioning have pleiotropic effects, the precise role of intestinal barrier loss in GVHD pathogenesis remains unclear. We developed GVHD models that allowed us to isolate the specific contributions of distinct pretransplant variables. Intestinal damage was required for the induction of minor mismatch [major histocompatibility complex (MHC)-matched] GVHD, but was not necessary for major mismatch GVHD, demonstrating fundamental pathogenic distinctions between these forms of disease. Moreover, recipient natural killer (NK) cells prevented minor mismatch GVHD by limiting expansion and target organ infiltration of alloreactive T cells via a perforin-dependent mechanism, revealing an immunoregulatory function of MHC-matched recipient NK cells in GVHD. Minor mismatch GVHD required MyD88-mediated Toll-like receptor 4 (TLR4) signaling on donor cells, and intestinal damage could be bypassed by parenteral lipopolysaccharide (LPS) administration, indicating a critical role for the influx of bacterial components triggered by intestinal barrier loss. In all, the data demonstrate that pretransplant conditioning plays a dual role in promoting minor mismatch GVHD by both depleting recipient NK cells and inducing intestinal barrier loss.
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http://dx.doi.org/10.1126/scitranslmed.3008941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161673PMC
July 2014

PD-1 regulates extrathymic regulatory T-cell differentiation.

Eur J Immunol 2014 Sep 18;44(9):2603-16. Epub 2014 Aug 18.

Department of Medicine, University of Chicago Comprehensive Cancer Center, Chicago, IL, USA.

Treg cells and the programed death-1/programed death ligand-1 (PD-1/PD-L1) pathway are both critical for maintaining peripheral tolerance to self-Ags. A significant subset of Treg cells constitutively expresses PD-1, which prompted an investigation into the role of PD-1/PD-L1 interactions in Treg-cell development, function, and induction in vivo. The phenotype and abundance of Treg cells was not significantly altered in PD-1-deficient mice. The thymic development of polyclonal and monospecific Treg cells was not negatively impacted by PD-1 deficiency. The suppressive function of PD-1(-/-) Treg cells was similar to their PD-1(+/+) counterparts both in vitro and in vivo. However, in three different in vivo experimental settings, PD-1(-/-) conventional CD4(+) T cells demonstrated a strikingly diminished tendency toward differentiation into peripherally induced Treg (pTreg) cells. Our results demonstrate that PD-1 is dispensable for thymic Treg-cell development and suppressive function, but is critical for the extrathymic differentiation of pTreg cells in vivo. These data suggest that Ab blockade of the PD-1/PD-L1 pathway may augment T-cell responses by acting directly on conventional T cells, and also by suppressing the differentiation of pTreg cells.
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http://dx.doi.org/10.1002/eji.201344423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165701PMC
September 2014

Shaping the repertoire of tumor-infiltrating effector and regulatory T cells.

Immunol Rev 2014 May;259(1):245-58

Department of Pathology, University of Chicago, Chicago, IL, USA.

Many tumors express antigens that can be specifically or selectively recognized by T lymphocytes, suggesting that T-cell-mediated immunity may be harnessed for the immunotherapy of cancer. However, since tumors originate from normal cells and evolve within the context of self-tissues, the immune mechanisms that prevent the autoimmune attack of normal tissues function in parallel to restrict anti-tumor immunity. In particular, the purging of autoreactive T cells and the development of immune-suppressive regulatory T cells (Tregs) are thought to be major barriers impeding anti-tumor immune responses. Here, we discuss current understanding regarding the antigens recognized by tumor-infiltrating T-cell populations, the mechanisms that shape the repertoire of these cells, and the role of the transcription factor autoimmune regulator (Aire) in these processes. Further elucidation of these principles is likely to be critical for optimizing emerging cancer immunotherapies, and for the rational design of novel therapies exhibiting robust anti-tumor activity with limited toxicity.
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http://dx.doi.org/10.1111/imr.12166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122093PMC
May 2014

Tumor antigenicity revealed.

Authors:
Peter A Savage

Trends Immunol 2014 Feb 15;35(2):47-8. Epub 2014 Jan 15.

Department of Pathology, University of Chicago, Chicago, IL 60605, USA. Electronic address:

The extent to which mutated peptide antigens encoded by somatic mutations contribute to tumor antigenicity in human cancer patients has been unclear. Two recent studies using tumor exome sequencing to predict candidate mutated antigens provide insight into this question.
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http://dx.doi.org/10.1016/j.it.2014.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932747PMC
February 2014

Organ-specific regulatory T cells of thymic origin are expanded in murine prostate tumors.

Oncoimmunology 2013 Jul 7;2(7):e24898. Epub 2013 May 7.

Department of Pathology; University of Chicago; Chicago, IL USA.

Little is known about the relative contributions of self-specific regulatory T cells (Tregs) of thymic origin and induced Tregs generated extrathymically to the pool of tumor-infiltrating Tregs. We have recently demonstrated that thymic-derived Tregs reactive to a prostate-associated self antigen are highly and recurrently enriched within oncogene-driven murine prostate cancers.
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http://dx.doi.org/10.4161/onci.24898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782164PMC
July 2013

Aire-dependent thymic development of tumor-associated regulatory T cells.

Science 2013 Mar;339(6124):1219-24

Department of Pathology, University of Chicago, Chicago, IL 60637, USA.

Despite considerable interest in the modulation of tumor-associated Foxp3(+) regulatory T cells (T(regs)) for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. We identified an endogenous population of antigen-specific T(regs) (termed MJ23 T(regs)) found recurrently enriched in the tumors of mice with oncogene-driven prostate cancer. MJ23 T(regs) were not reactive to a tumor-specific antigen but instead recognized a prostate-associated antigen that was present in tumor-free mice. MJ23 T(regs) underwent autoimmune regulator (Aire)-dependent thymic development in both male and female mice. Thus, Aire-mediated expression of peripheral tissue antigens drives the thymic development of a subset of organ-specific T(regs), which are likely coopted by tumors developing within the associated organ.
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http://dx.doi.org/10.1126/science.1233913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622085PMC
March 2013

Immune reconstitution after combined haploidentical and umbilical cord blood transplant.

Leuk Lymphoma 2013 Jun 1;54(6):1242-9. Epub 2013 Mar 1.

Section of Hematology/Oncology, Department of Medicine, The University of Chicago Medical Center, Chicago, IL, USA.

Umbilical cord blood (UCB) stem cells are frequently employed for allogeneic stem cell transplant, but delayed myeloid and lymphoid immune reconstitution leads to increased risk of infections. We recently reported the clinical results of 45 patients enrolled on a pilot study combining UCB with a human leukocyte antigen (HLA)-haploidentical donor with reduced-intensity conditioning who showed rapid neutrophil and platelet recovery. We report here preliminary immune reconstitution data of these patients. Patients were assessed for lymphocyte subsets, T-cell diversity, Cylex ImmuKnow assay and serological response to pneumococcal vaccination. Natural killer (NK)-cell and B-cell reconstitution were rapid at 1 month and 3 months, respectively. T-cell recovery was delayed, with a gradual increase in the number of T-cells starting around 6 months post-transplant, and was characterized by a diverse polyclonal T-cell repertoire. Overall, immune reconstitution after haplo-cord transplant is similar to that seen after cord blood transplant, despite infusion of much lower cord blood cell dose.
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http://dx.doi.org/10.3109/10428194.2012.739688DOI Listing
June 2013

Basic principles of tumor-associated regulatory T cell biology.

Trends Immunol 2013 Jan 19;34(1):33-40. Epub 2012 Sep 19.

Department of Pathology, University of Chicago, Chicago, IL 60637, USA.

Due to the critical role of forkhead box (Fox)p3(+) regulatory T cells (Tregs) in the regulation of immunity and the enrichment of Tregs within many human tumors, several emerging therapeutic strategies for cancer involve the depletion or modulation of Tregs, with the aim of eliciting enhanced antitumor immune responses. Here, we review recent advances in understanding of the fundamental biology of Tregs, and discuss the implications of these findings for current models of tumor-associated Treg biology. In particular, we discuss the context-dependent functional diversity of Tregs, the developmental origins of these cells, and the nature of the antigens that they recognize within the tumor environment. In addition, we highlight critical areas of focus for future research.
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http://dx.doi.org/10.1016/j.it.2012.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534814PMC
January 2013

T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-β1 cytokine.

Immunity 2011 Jul 14;35(1):123-34. Epub 2011 Jul 14.

Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Tolerance induction in T cells takes place in most tumors and is thought to account for tumor evasion from immune eradication. Production of the cytokine TGF-β is implicated in immunosuppression, but the cellular mechanism by which TGF-β induces T cell dysfunction remains unclear. With a transgenic model of prostate cancer, we showed that tumor development was not suppressed by the adaptive immune system, which was associated with heightened TGF-β signaling in T cells from the tumor-draining lymph nodes. Blockade of TGF-β signaling in T cells enhanced tumor antigen-specific T cell responses and inhibited tumor development. Surprisingly, T cell- but not Treg cell-specific ablation of TGF-β1 was sufficient to augment T cell cytotoxic activity and blocked tumor growth and metastases. These findings reveal that T cell production of TGF-β1 is an essential requirement for tumors to evade immunosurveillance independent of TGF-β produced by tumors.
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http://dx.doi.org/10.1016/j.immuni.2011.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430371PMC
July 2011

Recognition of a ubiquitous self antigen by prostate cancer-infiltrating CD8+ T lymphocytes.

Science 2008 Jan;319(5860):215-20

Department of Immunology, Howard Hughes Medical Institute, and Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY 10021, USA.

Substantial evidence exists that many tumors can be specifically recognized by CD8+ T lymphocytes. The definition of antigens targeted by these cells is paramount for the development of effective immunotherapeutic strategies for treating human cancers. In a screen for endogenous tumor-associated T cell responses in a primary mouse model of prostatic adenocarcinoma, we identified a naturally arising CD8+ T cell response that is reactive to a peptide derived from histone H4. Despite the ubiquitous nature of histones, T cell recognition of histone H4 peptide was specifically associated with the presence of prostate cancer in these mice. Thus, the repertoire of antigens recognized by tumor-infiltrating T cells is broader than previously thought and includes peptides derived from ubiquitous self antigens that are normally sequestered from immune detection.
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http://dx.doi.org/10.1126/science.1148886DOI Listing
January 2008
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