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

Abstract

Background 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. Methods 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 FH , T H 1, and T H 17/T H 22 using RNA flow cytometric fluorescence in situ hybridization (FISH). We compared increase in cytokine expression upon ICB across functions and patient status. Findings 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 H 1- and T H 17/T H 22-, but not T FH -related functions, increased. Cells co-expressing T H 1 and T FH 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. Interpretation 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. Funding NIH, CIHR, CFI, FRQS

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