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Peripherally induced brain tissue-resident memory CD8⁺ T cells mediate protection against CNS infection.

ABSTRACT: The central nervous system (CNS) is classically viewed as immune-privileged; however, recent advances highlight interactions between the peripheral immune system and CNS in controlling infections and tissue homeostasis. Tissue-resident memory (T_RM) CD8⁺ T cells in the CNS are generated after brain infections, but it is unknown whether CNS infection is required to generate brain T_RM cells. We show that peripheral infections generate antigen-specific CD8⁺ memory T cells in the brain that adopt a unique T_RM signature. Upon depletion of circulating and perivascular memory T cells, this brain signature was enriched and the surveilling properties of brain T_RM cells was revealed by intravital imaging. Notably, peripherally induced brain T_RM cells showed evidence of rapid activation and enhanced cytokine production and mediated protection after brain infections. These data reveal that peripheral immunizations can generate brain T_RM cells and will guide potential use of T cells as therapeutic strategies against CNS infections and neurological diseases.

SUBMITTER: Urban SL

PROVIDER: S-EPMC7381383 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Peripherally induced brain tissue-resident memory CD8+ T cells mediate protection against CNS infection.

Urban Stina L SL Jensen Isaac J IJ Shan Qiang Q Pewe Lecia L LL Xue Hai-Hui HH Badovinac Vladimir P VP Harty John T JT

Nature immunology 20200622 8

The central nervous system (CNS) is classically viewed as immune-privileged; however, recent advances highlight interactions between the peripheral immune system and CNS in controlling infections and tissue homeostasis. Tissue-resident memory (TRM) CD8+ T cells in the CNS are generated after brain infections, but it is unknown whether CNS infection is required to generate brain TRM cells. We show that peripheral infections generate antigen-specific CD8+</sup ...[more]

PMID: 32572242

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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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Peripherally induced brain tissue-resident memory CD8⁺ T cells mediate protection against CNS infection.

Publications

Peripherally induced brain tissue-resident memory CD8<sup>+</sup> T cells mediate protection against CNS infection.

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