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Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8⁺ tissue-resident memory T cells.

ABSTRACT: Elevated gene expression of the costimulatory receptor Icos is a hallmark of CD8⁺ tissue-resident memory (Trm) T cells. Here, we examined the contribution of ICOS in Trm cell differentiation. Upon transfer into WT mice, Icos^-/- CD8⁺ T cells exhibited defective Trm generation but produced recirculating memory populations normally. ICOS deficiency or ICOS-L blockade compromised establishment of CD8⁺ Trm cells but not their maintenance. ICOS ligation during CD8⁺ T cell priming did not determine Trm induction; rather, effector CD8⁺ T cells showed reduced Trm differentiation after seeding into Icosl^-/- mice. Icos^YF/YF CD8⁺ T cells were compromised in Trm generation, indicating a critical role for PI3K signaling. Modest transcriptional changes in the few Icos^-/- Trm cells suggest that ICOS-PI3K signaling primarily enhances the efficiency of CD8⁺ T cell tissue residency. Thus, local ICOS signaling promotes production of Trm cells, providing insight into the contribution of costimulatory signals in the generation of tissue-resident populations.

SUBMITTER: Peng C

PROVIDER: S-EPMC8755622 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8+ tissue-resident memory T cells.

Peng Changwei C Huggins Matthew A MA Wanhainen Kelsey M KM Knutson Todd P TP Lu Hanbin H Georgiev Hristo H Mittelsteadt Kristen L KL Jarjour Nicholas N NN Wang Haiguang H Hogquist Kristin A KA Campbell Daniel J DJ Borges da Silva Henrique H Jameson Stephen C SC

Immunity 20211220 1

Elevated gene expression of the costimulatory receptor Icos is a hallmark of CD8+ tissue-resident memory (Trm) T cells. Here, we examined the contribution of ICOS in Trm cell differentiation. Upon transfer into WT mice, Icos-/- CD8+ T cells exhibited defective Trm generation but produced recirculating memory populations normally. ICOS deficiency or ICOS-L blockade compromised establishment of CD8+ Trm cells but not their maintenance. ICOS ligation duri ...[more]

PMID: 34932944

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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.

Dataset Information

Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8⁺ tissue-resident memory T cells.

Publications

Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8<sup>+</sup> tissue-resident memory T cells.

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