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1.
Immunohorizons ; 4(1): 14-22, 2020 01 23.
Article in English | MEDLINE | ID: mdl-31974109

ABSTRACT

Mucosal-associated invariant T (MAIT) cells acquire effector function in response to proinflammatory signals, which synergize with TCR-mediated signals. We asked if cell-intrinsic regulatory mechanisms exist to curtail MAIT cell effector function akin to the activation-induced expression of inhibitory receptors by conventional T cells. We examined human MAIT cells from blood and oral mucosal tissues by RNA sequencing and found differential expression of immunoregulatory genes, including CTLA-4, by MAIT cells isolated from tissue. Using an ex vivo experimental setup, we demonstrate that inflammatory cytokines were sufficient to induce CTLA-4 expression on the MAIT cell surface in the absence of TCR signals. Even brief exposure to the cytokines IL-12, IL-15, and IL-18 was sufficient for sustained CTLA-4 expression by MAIT cells. These data suggest that control of CTLA-4 expression is fundamentally different between MAIT cells and conventional T cells. We propose that this mechanism serves to limit MAIT cell-mediated tissue damage.


Subject(s)
Antigens, Surface/immunology , CD8-Positive T-Lymphocytes/immunology , CTLA-4 Antigen/immunology , Cytokines/immunology , Mucosal-Associated Invariant T Cells/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Blood/immunology , Female , Gene Expression/immunology , Humans , Inflammation/genetics , Male , Middle Aged , Mucous Membrane/immunology , Receptors, Antigen, T-Cell/immunology
2.
Sci Transl Med ; 11(521)2019 12 04.
Article in English | MEDLINE | ID: mdl-31801887

ABSTRACT

CCR5 is thought to play a central role in orchestrating migration of cells in response to inflammation. CCR5 antagonists can reduce inflammatory disease processes, which has led to an increased interest in using CCR5 antagonists in a wide range of inflammation-driven diseases. Paradoxically, these antagonists appear to function without negatively affecting host immunity at barrier sites. We reasoned that the resolution to this paradox may lie in the CCR5+ T cell populations that permanently reside in tissues. We used a single-cell analysis approach to examine the human CCR5+ T cell compartment in the blood, healthy, and inflamed mucosal tissues to resolve these seemingly contradictory observations. We found that 65% of the CD4 tissue-resident memory T (TRM) cell compartment expressed CCR5. These CCR5+ TRM cells were enriched in and near the epithelial layer and not only limited to TH1-type cells but also contained a large TH17-producing and a stable regulatory T cell population. The CCR5+ TRM compartment was stably maintained even in inflamed tissues including the preservation of TH17 and regulatory T cell populations. Further, using tissues from the CHARM-03 clinical trial, we found that CCR5+ TRM are preserved in human mucosal tissue during treatment with the CCR5 antagonist Maraviroc. Our data suggest that the human CCR5+ TRM compartment is functionally and spatially equipped to maintain barrier immunity even in the absence of CCR5-mediated, de novo T cell recruitment from the periphery.


Subject(s)
Cell Compartmentation , Inflammation/immunology , Receptors, CCR5/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cell Compartmentation/drug effects , Cytokines/biosynthesis , Female , Humans , Lectins, C-Type/metabolism , Lymphocyte Subsets/drug effects , Lymphocyte Subsets/immunology , Male , Maraviroc/pharmacology , Middle Aged , Mouth Mucosa/drug effects , Mouth Mucosa/immunology , Mouth Mucosa/pathology , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/drug effects , Th17 Cells/drug effects , Th17 Cells/immunology , Transcriptome/genetics , Young Adult
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