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Discipline in Stages: Regulating CD8⁺ Resident Memory T Cells.

ABSTRACT: Resident memory CD8⁺ T (T_RM) cells are a lymphocyte lineage distinct from circulating memory CD8⁺ T cells. T_RM lodge within peripheral tissues and secondary lymphoid organs where they provide rapid, local protection from pathogens and control tumor growth. However, dysregulation of CD8⁺ T_RM formation and/or activation may contribute to the pathogenesis of autoimmune diseases. Intrinsic mechanisms, including transcriptional networks and inhibitory checkpoint receptors control T_RM differentiation and response. Additionally, extrinsic stimuli such as cytokines, cognate antigen, fatty acids, and damage signals regulate T_RM formation, maintenance, and expansion. In this review, we will summarize knowledge of CD8⁺ T_RM generation and highlight mechanisms that regulate the persistence and responses of heterogeneous T_RM populations in different tissues and distinct microenvironments.

SUBMITTER: Mora-Buch R

PROVIDER: S-EPMC8017121 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Discipline in Stages: Regulating CD8+ Resident Memory T Cells.

Mora-Buch Rut R Bromley Shannon K SK

Frontiers in immunology 20210319

Resident memory CD8+ T (TRM) cells are a lymphocyte lineage distinct from circulating memory CD8+ T cells. TRM lodge within peripheral tissues and secondary lymphoid organs where they provide rapid, local protection from pathogens and control tumor growth. However, dysregulation of CD8+ TRM formation and/or activation may contribute to the pathogenesis of autoimmune diseases. Intrinsic mechanisms, including transcriptional network ...[more]

PMID: 33815352

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Project description:IntroductionDespite recent advances in immunotherapy for hepatocellular carcinoma (HCC), the overall modest response rate underscores the need for a better understanding of the tumor microenvironment (TME) of HCC. We have previously shown that CD38 is widely expressed on tumor-infiltrating leukocytes (TILs), predominantly on CD3+ T cells and monocytes. However, its specific role in the HCC TME remains unclear.MethodsIn this current study, we used cytometry time-of-flight (CyTOF), bulk RNA sequencing on sorted T cells, and single-cell RNA (scRNA) sequencing to interrogate expression of CD38 and its correlation with T cell exhaustion in HCC samples. We also employed multiplex immunohistochemistry (mIHC) for validating our findings.ResultsFrom CyTOF analysis, we compared the immune composition of CD38-expressing leukocytes in TILs, non-tumor tissue-infiltrating leukocytes (NIL), and peripheral blood mononuclear cells (PBMC). We identified CD8+ T cells as the dominant CD38-expressing TILs and found that CD38 expression was significantly higher in CD8+ TRM in TILs than in NILs. Furthermore, through transcriptomic analysis on sorted CD8+ TRM from HCC tumors, we observed a higher expression of CD38 along with T cell exhaustion genes, including PDCD1 and CTLA4, compared to the circulating memory CD8 T cells from PBMC. This was validated by scRNA sequencing that revealed co-expression of CD38 with PDCD1, CTLA4, and ITGAE (CD103) in T cells from HCC tumors. The protein co-expression of CD38 and PD-1 on CD8+ T cells was further demonstrated by mIHC on HCC FFPE tissues, marking CD38 as a T cell co-exhaustion marker in HCC. Lastly, the higher proportions of CD38+PD-1+ CD8+ T cells and CD38+PD-1+ TRM were significantly associated with the higher histopathological grades of HCC, indicating its role in the aggressiveness of the disease.ConclusionTaken together, the concurrent expression of CD38 with exhaustion markers on CD8+ TRM underpins its role as a key marker of T cell exhaustion and a potential therapeutic target for restoring cytotoxic T cell function in HCC.

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Discipline in Stages: Regulating CD8⁺ Resident Memory T Cells.

Publications

Discipline in Stages: Regulating CD8<sup>+</sup> Resident Memory T Cells.

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