Publications by authors named "Priscila Muñoz-Sandoval"

10 Publications

  • Page 1 of 1

Global absence and targeting of protective immune states in severe COVID-19.

Nature 2021 03 25;591(7848):124-130. Epub 2021 Jan 25.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs) across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.
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http://dx.doi.org/10.1038/s41586-021-03234-7DOI Listing
March 2021

Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8 T cells in autoimmunity and cancer.

J Allergy Clin Immunol 2020 Dec 9. Epub 2020 Dec 9.

Department of Dermatology, University of California San Francisco, San Francisco, Calif. Electronic address:

Background: Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8 T cells have been identified as pathogenic drivers.

Objective: Our study focused on comprehensively characterizing the phenotypic variation of CD8 T cells in psoriatic lesions.

Methods: We used single-cell RNA sequencing to compare CD8 T-cell transcriptomic heterogeneity between psoriatic and healthy skin.

Results: We identified 11 transcriptionally diverse CD8 T-cell subsets in psoriatic and healthy skin. Among several inflammatory subsets enriched in psoriatic skin, we observed 2 Tc17 cell subsets that were metabolically divergent, were developmentally related, and expressed CXCL13, which we found to be a biomarker of psoriasis severity and which achieved comparable or greater accuracy than IL17A in a support vector machine classifier of psoriasis and healthy transcriptomes. Despite high coinhibitory receptor expression in the Tc17 cell clusters, a comparison of these cells with melanoma-infiltrating CD8 T cells revealed upregulated cytokine, cytolytic, and metabolic transcriptional activity in the psoriatic cells that differed from an exhaustion program.

Conclusion: Using high-resolution single-cell profiling in tissue, we have uncovered the diverse landscape of CD8 T cells in psoriatic and healthy skin, including 2 nonexhausted Tc17 cell subsets associated with disease severity.
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http://dx.doi.org/10.1016/j.jaci.2020.11.028DOI Listing
December 2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

bioRxiv 2020 Oct 29. Epub 2020 Oct 29.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.

One Sentence Summary: In severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.
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http://dx.doi.org/10.1101/2020.10.28.359935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605559PMC
October 2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

Res Sq 2020 Oct 28. Epub 2020 Oct 28.

Department of Pathology, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, CA 94143-0511, USA.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a wholeblood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferonstimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and autodirected antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.
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http://dx.doi.org/10.21203/rs.3.rs-97042/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605560PMC
October 2020

Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues.

JCI Insight 2019 12 19;4(24). Epub 2019 Dec 19.

Department of Dermatology.

Distinct subsets of Tregs reside in nonlymphoid tissues where they mediate unique functions. To interrogate the biology of tissue Tregs in human health and disease, we phenotypically and functionally compared healthy skin Tregs with those in peripheral blood, inflamed psoriatic skin, and metastatic melanoma. The mitochondrial enzyme, arginase 2 (ARG2), was preferentially expressed in Tregs in healthy skin, increased in Tregs in metastatic melanoma, and reduced in Tregs from psoriatic skin. ARG2 enhanced Treg suppressive capacity in vitro and conferred a selective advantage for accumulation in inflamed tissues in vivo. CRISPR-mediated deletion of this gene in primary human Tregs was sufficient to skew away from a tissue Treg transcriptional signature. Notably, the inhibition of ARG2 increased mTOR signaling, whereas the overexpression of this enzyme suppressed it. Taken together, our results suggest that Tregs express ARG2 in human tissues to both regulate inflammation and enhance their metabolic fitness.
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http://dx.doi.org/10.1172/jci.insight.129756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975275PMC
December 2019

Regulatory T cells in skin are uniquely poised to suppress profibrotic immune responses.

Sci Immunol 2019 09;4(39)

Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.

At the center of fibrosing diseases is the aberrant activation of tissue fibroblasts. The cellular and molecular mechanisms of how the immune system augments fibroblast activation have been described; however, little is known about how the immune system controls fibroblast function in tissues. Here, we identify regulatory T cells (T) as important regulators of fibroblast activation in skin. Bulk cell and single-cell analysis of T in murine skin and lungs revealed that T in skin are transcriptionally distinct and skewed toward T helper 2 (T2) differentiation. When compared with T in lung, skin T preferentially expressed high levels of GATA3, the master T2 transcription factor. Genes regulated by GATA3 were highly enriched in skin "T2 T" subsets. In functional experiments, T depletion resulted in a preferential increase in T2 cytokine production in skin. Both acute depletion and chronic reduction of T resulted in spontaneous skin fibroblast activation, profibrotic gene expression, and dermal fibrosis, all of which were exacerbated in a bleomycin-induced murine model of skin sclerosis. Lineage-specific deletion of in T resulted in an exacerbation of T2 cytokine secretion that was preferential to skin, resulting in enhanced fibroblast activation and dermal fibrosis. Together, we demonstrate that T play a critical role in regulating fibroblast activation in skin and do so by expressing a unique tissue-restricted transcriptional program that is mediated, at least in part, by GATA3.
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http://dx.doi.org/10.1126/sciimmunol.aaw2910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848056PMC
September 2019

The TNFRSF members CD27 and OX40 coordinately limit T17 differentiation in regulatory T cells.

Sci Immunol 2018 12;3(30)

Department of Dermatology, University of California, San Francisco, CA 94143, USA.

Regulatory T cells (T) are closely related to T17 cells and use aspects of the T17-differentiation program for optimal immune regulation. In several chronic inflammatory human diseases, T express IL-17A, suggesting that dysregulation of T17-associated pathways in T may result in either loss of suppressive function and/or conversion into pathogenic cells. The pathways that regulate the T17 program in T are poorly understood. We have identified two TNF receptor superfamily (TNFRSF) members, CD27 and OX40, that are preferentially expressed by skin-resident T Both CD27 and OX40 signaling suppressed the expression of T17-associated genes from T in a cell-intrinsic manner in vitro and in vivo. However, only OX40 played a nonredundant role in promoting T accumulation. T that lacked both CD27 and OX40 were defective in controlling skin inflammation and expressed high levels of IL-17A, as well as the master T17 transcription factor, RORγt. Last, we found that CD27 expression was inversely correlated with T IL-17 production in skin of patients with psoriasis and hidradenitis suppurativa. Together, our results suggest that TNFRSF members play both redundant and distinct roles in regulating T plasticity in tissues.
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http://dx.doi.org/10.1126/sciimmunol.aau2042DOI Listing
December 2018

RNA-seq and flow-cytometry of conventional, scalp, and palmoplantar psoriasis reveal shared and distinct molecular pathways.

Sci Rep 2018 07 27;8(1):11368. Epub 2018 Jul 27.

Department of Dermatology, University of California, San Francisco, San Francisco, CA, United States.

It has long been recognized that anatomic location is an important feature for defining distinct subtypes of plaque psoriasis. However, little is known about the molecular differences between scalp, palmoplantar, and conventional plaque psoriasis. To investigate the molecular heterogeneity of these psoriasis subtypes, we performed RNA-seq and flow cytometry on skin samples from individuals with scalp, palmoplantar, and conventional plaque psoriasis, along with samples from healthy control patients. We performed differential expression analysis and network analysis using weighted gene coexpression network analysis (WGCNA). Our analysis revealed a core set of 763 differentially expressed genes common to all sub-types of psoriasis. In contrast, we identified 605, 632, and 262 genes uniquely differentially expressed in conventional, scalp, and palmoplantar psoriasis, respectively. WGCNA and pathway analysis revealed biological processes for the core genes as well as subtype-specific genes. Flow cytometry analysis revealed a shared increase in the percentage of CD4+ T regulatory cells in all psoriasis subtypes relative to controls, whereas distinct psoriasis subtypes displayed differences in IL-17A, IFN-gamma, and IL-22 production. This work reveals the molecular heterogeneity of plaque psoriasis and identifies subtype-specific signaling pathways that will aid in the development of therapy that is appropriate for each subtype of plaque psoriasis.
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http://dx.doi.org/10.1038/s41598-018-29472-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063960PMC
July 2018

Skin-infiltrating, interleukin-22-producing T cells differentiate pediatric psoriasis from adult psoriasis.

J Am Acad Dermatol 2017 Sep 16;77(3):417-424. Epub 2017 Jun 16.

Department of Dermatology, University of California, San Francisco, California.

Background: Evidence from adult psoriasis studies implicates an imbalance between regulatory and effector T cells, particularly T-17-producing T cells, in the pathogenesis of psoriasis. Little is known about the immunopathology of psoriasis in children.

Objective: We sought to functionally characterize the inflammatory cell profiles of psoriatic plaques from pediatric patients and compare them with healthy, age-matched controls and adult psoriasis patients.

Methods: Skin samples from pediatric psoriasis patients and healthy controls were analyzed by multiparameter flow cytometry to determine the dominant immune cell subsets present and cytokines produced.

Results: Lesional tissue from pediatric psoriasis patients had significantly increased interleukin (IL) 22 derived from CD4 and CD8 cells compared with the tissues from healthy pediatric controls and adult psoriasis patients. Tissue from pediatric psoriasis patients had significantly less elevation of IL-17 derived from CD4 and CD8 cells compared with the tissue from adult psoriasis patients. In contrast with the lesions from adult patients, lesional skin in pediatric patients with psoriasis did not have increases in regulatory T cells.

Limitations: This is a pilot study, thus the sample size is small.

Conclusion: Significant differences in IL-17 and IL-22 expression were observed in the pediatric psoriasis patients compared with pediatric healthy controls and adult psoriasis patients. IL-22 might be relevant in the pathogenesis of pediatric psoriasis and represents a potential treatment target unique to pediatric psoriasis.
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http://dx.doi.org/10.1016/j.jaad.2017.05.017DOI Listing
September 2017

Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma.

J Clin Invest 2016 09 15;126(9):3447-52. Epub 2016 Aug 15.

Background: Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options.

Methods: We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype.

Results: Increasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs.

Conclusions: Our data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition.

Funding: This work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.
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http://dx.doi.org/10.1172/JCI87324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004965PMC
September 2016