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Differentiation of exhausted CD8⁺ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

ABSTRACT: T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8⁺ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory.

SUBMITTER: Tonnerre P

PROVIDER: S-EPMC8323980 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Differentiation of exhausted CD8<sup>+</sup> T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

Tonnerre Pierre P Wolski David D Subudhi Sonu S Aljabban Jihad J Hoogeveen Ruben C RC Damasio Marcos M Drescher Hannah K HK Bartsch Lea M LM Tully Damien C DC Sen Debattama R DR Bean David J DJ Brown Joelle J Torres-Cornejo Almudena A Robidoux Maxwell M Kvistad Daniel D Alatrakchi Nadia N Cui Ang A Lieb David D Cheney James A JA Gustafson Jenna J Lewis-Ximenez Lia L LL Massenet-Regad Lucile L Eisenhaure Thomas T Aneja Jasneet J Haining W Nicholas WN Chung Raymond T RT Hacohen Nir N Allen Todd M TM Kim Arthur Y AY Lauer Georg M GM

Nature immunology 20210726 8

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8<sup>+</sup> T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally sta ...[more]

PMID: 34312544

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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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Differentiation of exhausted CD8⁺ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

Publications

Differentiation of exhausted CD8<sup>+</sup> T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

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Dataset Information

Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

Publications

Differentiation of exhausted CD8<sup>+</sup> T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Differentiation of exhausted CD8⁺ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory.