Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function.

Details

Serval ID
serval:BIB_79D15E9CC965
Type
Article: article from journal or magazin.
Collection
Publications
Title
Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function.
Journal
EBioMedicine
Author(s)
Brunet-Ratnasingham E., Morou A., Dubé M., Niessl J., Baxter A.E., Tastet O., Brassard N., Ortega-Delgado G., Charlebois R., Freeman G.J., Tremblay C., Routy J.P., Kaufmann D.E.
ISSN
2352-3964 (Electronic)
ISSN-L
2352-3964
Publication state
Published
Issued date
10/2022
Peer-reviewed
Oui
Volume
84
Pages
104254
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Immune checkpoint blockade (ICB) partially reverses the dysfunctional state of antigen-specific T cell in chronic infections. However, its impact on the diverse subsets of CD4+ T cells in humans is largely unknown.
We examined immune checkpoint (IC) expression and function in HIV-specific CD4+ T cells of viremic individuals (≥5000 vRNA cp/ml, n = 17) prior to ART and persons with spontaneous (n = 11) or therapy-induced (n = 16) viral suppression (<40 cp/ml). We investigated IC patterns associated with exhaustion-related transcription factors and chemokine receptors using activation-induced marker assays. We determined effector functions representative of T <sub>FH</sub> , T <sub>H</sub> 1, and T <sub>H</sub> 17/T <sub>H</sub> 22 using RNA flow cytometric fluorescence in situ hybridization (FISH). We compared increase in cytokine expression upon ICB across functions and patient status.
Expression of dysfunction-related molecules, such as transcription factors and ICs PD-1, TIGIT, and CD200, followed a hierarchy associated with infection status and effector profile. In vitro responsiveness to PD-L1 blockade varied with defined functions rather than IC levels: frequencies of cells with T <sub>H</sub> 1- and T <sub>H</sub> 17/T <sub>H</sub> 22-, but not T <sub>FH</sub> -related functions, increased. Cells co-expressing T <sub>H</sub> 1 and T <sub>FH</sub> functions showed response to ICB, suggesting that the cell's state rather than function dictates responsiveness to PD-L1 blockade. Response to PD-L1 blockade was strongest in viremic participants and reduced after ART initiation.
Our data highlight a polarization-specific regulation of IC expression and differing sensitivities of antigen-specific T helper subsets to PD-1-mediated inhibition. This heterogeneity may direct and constrain ICB efficacy in restoring CD4+ T cell function in HIV infection and other diseases.
NIH, CIHR, CFI, FRQS.
Keywords
B7-H1 Antigen/metabolism, CD4-Positive T-Lymphocytes, Cytokines/metabolism, HIV Infections, Humans, Immune Checkpoint Inhibitors, In Situ Hybridization, Fluorescence, Programmed Cell Death 1 Receptor/genetics, Programmed Cell Death 1 Receptor/metabolism, RNA/therapeutic use, Receptors, Chemokine/metabolism, Receptors, Chemokine/therapeutic use, Receptors, Immunologic/metabolism, Transcription Factors/metabolism, CD4+ T cell subsets, HIV-specific CD4+ T cells, Immune checkpoint blockade, PD-1, T cell dysfunction, TOX
Pubmed
Web of science
Open Access
Yes
Create date
09/05/2023 12:59
Last modification date
29/11/2024 16:59
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