Dataset Information

CD4⁺ and CD8⁺ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG₄-related disease.

ABSTRACT:

Background

IgG₄-related disease (IgG₄-RD) is an immune-mediated fibrotic disorder that has been linked to CD4⁺ cytotoxic T lymphocytes (CD4⁺CTLs). The effector phenotype of CD4⁺CTLs and the relevance of both CD8⁺ cytotoxic T lymphocytes (CD8⁺CTLs) and apoptotic cell death remain undefined in IgG₄-RD.

Objective

We sought to define CD4⁺CTL heterogeneity, characterize the CD8⁺CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG₄-RD.

Methods

Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data.

Results

We establish that among circulating CD4⁺CTLs in IgG₄-RD, CD27^loCD28^loCD57^hi cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A-expressing CD8⁺CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8⁺ T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR.

Conclusions

CD4⁺CTLs and CD8⁺CTLs may induce apoptotic cell death in tissues of patients with IgG₄-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.

SUBMITTER: Perugino CA

PROVIDER: S-EPMC7704943 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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

CD4⁺ and CD8⁺ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG₄-related disease.

Background

Objective

Methods

Results

Conclusions

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease.

Background

Objective

Methods

Results

Conclusions

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OmicsDI is part of the ELIXIR infrastructure

Tweets

CD4⁺ and CD8⁺ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG₄-related disease.