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

By Elsa Brunet-Ratnasingham, Antigoni Morou, Mathieu Dube, Julia Niessl, Amy E. Baxter, Olivier Tastet, Nathalie Brassard, Gloria Ortega-Delgado, Roxanne Charlebois, Gordon J Freeman, Cecile Tremblay, Jean-Pierre Routy, Daniel E Kaufmann

Posted 24 Sep 2021
bioRxiv DOI: 10.1101/2021.09.23.461484

Background: Antigen-specific T cell impairment is observed in chronic infections. CD4+ T cells are diverse in phenotype and function; how their different lineages are impacted by inhibitory immune checkpoints (IC) is unknown. Methods: We examined IC expression and function in HIV-specific CD4+ T cells of viremic individuals prior to ART initiation and persons with spontaneous or therapy-induced viral suppression. We investigated IC patterns associated with exhaustion-related transcription factors and chemokine receptors using cytokine-independent activation-induced marker assays. We determined effector functions representative of TFH, TH1 and TH17/TH22 using ultra-sensitive RNA flow cytometric fluorescence in situ hybridization (FISH), and their response to IC blockade. Findings: The dysfunction-related transcription factor TOX was elevated in HIV-specific CD4+ T cells of viremic patients, and its expression was associated with lineage differentiation. We observed a hierarchy of PD-1, TIGIT and CD200 expression associated with both infection status and effector profile. In vitro responsiveness to PD-L1 blockade varied with defined CD4+ T cell functions rather than IC expression levels: frequencies of cells with TH1- and TH17/TH22-, but not TFH-related functions, increased. Response to PD-L1 blockade was strongest in viremic participants and reduced after ART initiation. Interpretation: Our data highlight a polarization-specific regulation of IC expression and differing sensitivities of antigen-specific Thelper subsets to PD-1-mediated inhibition. This heterogeneity may direct ICB efficacy on CD4+ T cells in HIV infection.

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