Dataset Information

CD49a Expression Defines Tissue-Resident CD8⁺ T Cells Poised for Cytotoxic Function in Human Skin.

ABSTRACT: Tissue-resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8⁺ Trm cells on a compartmental and functional basis. In human skin epithelia, CD8⁺CD49a⁺ Trm cells produced interferon-?, whereas CD8⁺CD49a^- Trm cells produced interleukin-17 (IL-17). In addition, CD8⁺CD49a⁺ Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response. In skin from patients with vitiligo, where melanocytes are eradicated locally, CD8⁺CD49a⁺ Trm cells that constitutively expressed perforin and granzyme B accumulated both in the epidermis and dermis. Conversely, CD8⁺CD49a^- Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease. Overall, CD49a expression delineates CD8⁺ Trm cell specialization in human epithelial barriers and correlates with the effector cell balance found in distinct inflammatory skin diseases.

SUBMITTER: Cheuk S

PROVIDER: S-EPMC5337619 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin.

Cheuk Stanley S Schlums Heinrich H Gallais Sérézal Irène I Martini Elisa E Chiang Samuel C SC Marquardt Nicole N Gibbs Anna A Detlofsson Ebba E Introini Andrea A Forkel Marianne M Höög Charlotte C Tjernlund Annelie A Michaëlsson Jakob J Folkersen Lasse L Mjösberg Jenny J Blomqvist Lennart L Ehrström Marcus M Ståhle Mona M Bryceson Yenan T YT Eidsmo Liv L

Immunity 20170214 2

Tissue-resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8+ Trm cells on a compartmental and functional basis. In human skin epithelia, CD8+CD49a+ Trm cells produced interferon-γ, whereas CD8+CD49a- Trm cells produced interleukin-17 (IL-17). In addition, CD8+CD49a+ Trm cells from healthy skin rapid ...[more]

PMID: 28214226

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Project description:Pulmonary fibrosis is a devastating disease with no effective treatments to cure, stop or reverse the unremitting, fatal fibrosis. A critical barrier to treating this disease is the lack of understanding of the pathways leading to fibrosis as well as those regulating the resolution of fibrosis. Fibrosis is the pathologic side of normal tissue repair that results when the normal wound healing programs go awry. Successful resolution of tissue injury requires several highly coordinated pathways, and this research focuses on the interplay between these overlapping pathways: immune effectors, inflammatory mediators and fibroproliferation in the resolution of fibrosis. Previously we have successfully prevented, mitigated, and even reversed established fibrosis using vaccinia vaccination immunotherapy in two models of murine lung fibrosis. The mechanism by which vaccinia reverses fibrosis is by vaccine induced lung specific Th1 skewed tissue resident memory (TRMs) in the lung. In this study, we isolated a population of vaccine induced TRMs - CD49a+ CD4+ T cells - that are both necessary and sufficient to reverse established pulmonary fibrosis. Using adoptive cellular therapy, we demonstrate that intratracheal administration of CD49a+ CD4+ TRMs into established fibrosis, reverses the fibrosis histologically, by promoting a decrease in collagen, and functionally, by improving lung function, without the need for vaccination. Furthermore, co-culture of in vitro derived CD49+ CD4+ human TRMs with human fibroblasts from individuals with idiopathic pulmonary fibrosis (IPF) results in the down regulation of IPF fibroblast collagen production. Lastly, we demonstrate in human IPF lung histologic samples that CD49a+ CD4+ TRMs, which can down regulate human IPF fibroblast function, fail to increase in the IPF lungs, thus potentially failing to promote resolution. Thus, we define a novel unappreciated role for tissue resident memory T cells in regulating established lung fibrosis to promote resolution of fibrosis and re-establish lung homeostasis. We demonstrate that immunotherapy, in the form of adoptive transfer of CD49a+ CD4+ TRMs into the lungs of mice with established fibrosis, not only stops progression of the fibrosis but more importantly reverses the fibrosis. These studies provide the insight and preclinical rationale for a novel paradigm shifting approach of using cellular immunotherapy to treat lung fibrosis.

Project description:CD49a+ tissue resident NK cells have been implicated in memory-like NK cell responses, but while this population is well-characterized in mice and in humans, they are poorly described in non-human primates (NHP) which are particularly critical for modeling human viral infections. Others and we have shown that memory-like NK cells are enriched in the liver and because of the importance of NHP in modeling HIV infection, understanding the immunobiology of CD49a+ NK cells in SIV-infected rhesus macaques is critical to explore the role of this cell type in retroviral infections. In this study mononuclear cells isolated from livers, spleens, and peripheral whole blood were analyzed in acutely and chronically lentivirus-infected and experimentally-naïve Indian rhesus macaques (RM). NK cells were then identified as CD45+CD14-CD20-CD3-NKG2A/C+ cells and characterized using multiparametric flow-cytometry. Our data show that in RM, CD49a+ NK cells increase in the liver following retroviral infections [median = 5.2% (naïve) vs. median = 9.48% (SIV+) or median = 16.8% (SHIV+)]. In contrast, there is little change in CD49a+ NK frequencies in whole blood or spleens of matched animals. In agreement with human and murine data we also observed that CD49a+ NK cells were predominantly Eomeslow T-betlow, though these frequencies are elevated in infected animal cohorts. Functionally, our data suggests that infection alters TNF-α, IFN-γ, and CD107a expression in stimulated CD49a+ NK cells. Specifically, our analyses found a decrease in CD49a+ CD107a+ TNFα+ IFNγ- NK cells, with a simultaneous increase in CD49a+ CD107a+ TNFα- IFNγ+ NK cells and the non-responsive CD49a+ CD107a- TNFα- IFNγ- NK cell population following infection, suggesting both pathogenic and inflammatory changes in the NK cell functional profile. Our data also identified significant global differences in polyfunctionality between CD49a+ NK cells in the naïve and chronic (SHIV+) cohorts. Our work provides the first characterization of CD49a+ NK cells in tissues from RM. The significant similarities between CD49a+ NK cells from RM and what is reported from human samples justifies the importance of studying CD49a+ NK cells in this species to support preclinical animal model research.

Dataset Information

CD49a Expression Defines Tissue-Resident CD8⁺ T Cells Poised for Cytotoxic Function in Human Skin.

Publications

CD49a Expression Defines Tissue-Resident CD8<sup>+</sup> T Cells Poised for Cytotoxic Function in Human Skin.

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