Dataset Information

Differential expression of inhibitory receptor NKG2A distinguishes disease-specific exhausted CD8⁺ T cells.

ABSTRACT: Exhausted CD8⁺ T (Tex) cells are caused by persistent antigenic stimulation during chronic viral infection or tumorigenesis. Tex cells upregulate and sustain the expressions of multiple immune inhibitory receptors (IRs). Blocking IRs of Tex cells, exemplified by PD-1, can partially restore their effector functions and thus lead to viral suppression or tumor remission. Tex cells derived from chronic viral infections share the expression spectrum of IRs with Tex cells derived from tumors; however, whether any IRs are selectively expressed by tumor-derived Tex cells or virus-derived Tex cells remains to be learnt. In the study, we found that Tex cells upregulate IR natural killer cell lectin-like receptor isoform A (NKG2A) specifically in the context of tumor but not chronic viral infection. Moreover, the NKG2A expression is attributed to tumor antigen recognition and thus bias expressed by tumor-specific Tex cells in the tumor microenvironment instead of their counterparts in the periphery. Such dichotomous NKG2A expression further dictates the differential responsiveness of Tex cells to NKG2A immune checkpoint blockade. Therefore, our study highlighted NKG2A as a disease-dependent IR and provided novel insights into the distinct regulatory mechanisms underlying T cell exhaustion between tumor and chronic viral infection.

SUBMITTER: Chen X

PROVIDER: S-EPMC8906559 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Differential expression of inhibitory receptor NKG2A distinguishes disease-specific exhausted CD8<sup>+</sup> T cells.

Chen Xiangyu X Lin Yao Y Yue Shuai S Yang Yang Y Wang Xinxin X Pan Zhiwei Z Yang Xiaofan X Gao Leiqiong L Zhou Jing J Li Zhirong Z Hu Li L Tang Jianfang J Wu Qing Q Wang Yifei Y Tian Qin Q Hao Yaxing Y Xu Lifan L Zhu Bo B Huang Qizhao Q Ye Lilin L

MedComm 20220110 1

Exhausted CD8<sup>+</sup> T (Tex) cells are caused by persistent antigenic stimulation during chronic viral infection or tumorigenesis. Tex cells upregulate and sustain the expressions of multiple immune inhibitory receptors (IRs). Blocking IRs of Tex cells, exemplified by PD-1, can partially restore their effector functions and thus lead to viral suppression or tumor remission. Tex cells derived from chronic viral infections share the expression spectrum of IRs with Tex cells derived from tumor ...[more]

PMID: 35281793

Similar Datasets

Project description:CD8+ cytotoxic T lymphocytes (CTLs) exert potent antiviral activity after HIV/SIV infection. However, efforts to harness the antiviral efficacy of CTLs for HIV/SIV prophylaxis and therapy have been severely hindered by two major problems: viral escape and exhaustion. By contrast, CTLs directed against human cytomegalovirus (HCMV), a ubiquitous chronic herpesvirus, seldom select for escape mutations and remain functional and refractory to exhaustion during chronic HCMV and HIV infection. Recently, attempts have been made to retarget HCMV-specific CTLs for cancer immunotherapy. We speculate that such a strategy may also be beneficial in the context of HIV/SIV infection, facilitating CTL-mediated control of HIV/SIV replication. As a preliminary assessment of the validity of this approach, we investigated the phenotypes and functionality of rhesus CMV (RhCMV)-specific CTLs in SIVmac239-infected Indian rhesus macaques (RMs), a crucial HIV animal model system. We recently identified two immunodominant, Mamu-A∗02-restricted CTL epitopes derived from RhCMV proteins and sought to evaluate the phenotypic and functional characteristics of these CTL populations in chronic SIVmac239 infection. We analyzed and directly compared RhCMV- and SIVmac239-specific CTLs during SIVmac239 infection in a cohort of Mamu-A∗01 + and Mamu-A∗02 + RMs. CTL populations specific for at least one of the RhCMV-derived CTL epitopes were detected in ten of eleven Mamu-A∗02 + animals tested, and both populations were detected in five of these animals. Neither RhCMV-specific CTL population exhibited significant changes in frequency, memory phenotype, granzyme B expression, exhaustion marker (PD-1 and CTLA-4) expression, or polyfunctionality between pre- and chronic SIVmac239 infection timepoints. In chronic SIVmac239 infection, RhCMV-specific CTLs exhibited higher levels of granzyme B expression and polyfunctionality, and lower levels of exhaustion marker expression, than SIVmac239-specific CTLs. Additionally, compared to SIVmac239-specific CTLs, greater proportions of RhCMV-specific CTLs were of the terminally differentiated effector memory phenotype (CD28- CCR7-) during chronic SIVmac239 infection. These results suggest that, in contrast to SIVmac239-specific CTLs, RhCMV-specific CTLs maintain their phenotypes and cytolytic effector functions during chronic SIVmac239 infection, and that retargeting RhCMV-specific CTLs might be a promising SIV immunotherapeutic strategy.

Dataset Information

Differential expression of inhibitory receptor NKG2A distinguishes disease-specific exhausted CD8⁺ T cells.

Publications

Differential expression of inhibitory receptor NKG2A distinguishes disease-specific exhausted CD8<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Differential expression of inhibitory receptor NKG2A distinguishes disease-specific exhausted CD8+ T cells.

Publications

Differential expression of inhibitory receptor NKG2A distinguishes disease-specific exhausted CD8<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Differential expression of inhibitory receptor NKG2A distinguishes disease-specific exhausted CD8⁺ T cells.