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Environmental cues regulate epigenetic reprogramming of airway-resident memory CD8⁺ T cells.

ABSTRACT: Tissue-resident memory T cells (T_RM cells) are critical for cellular immunity to respiratory pathogens and reside in both the airways and the interstitium. In the present study, we found that the airway environment drove transcriptional and epigenetic changes that specifically regulated the cytolytic functions of airway T_RM cells and promoted apoptosis due to amino acid starvation and activation of the integrated stress response. Comparison of airway T_RM cells and splenic effector-memory T cells transferred into the airways indicated that the environment was necessary to activate these pathways, but did not induce T_RM cell lineage reprogramming. Importantly, activation of the integrated stress response was reversed in airway T_RM cells placed in a nutrient-rich environment. Our data defined the genetic programs of distinct lung T_RM cell populations and show that local environmental cues altered airway T_RM cells to limit cytolytic function and promote cell death, which ultimately leads to fewer T_RM cells in the lung.

SUBMITTER: Hayward SL

PROVIDER: S-EPMC7044042 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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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Environmental cues regulate epigenetic reprogramming of airway-resident memory CD8⁺ T cells.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Environmental cues regulate epigenetic reprogramming of airway-resident memory CD8+ T cells.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Environmental cues regulate epigenetic reprogramming of airway-resident memory CD8⁺ T cells.