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

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.
Competing Interests: Declaration of interests G.J.F. has patents/pending royalties on the PD-1/PD-L1 pathway from Roche, Merck M.S.D., Bristol-Myers-Squibb, Merck K.G.A., Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, and NextPoint. GJF has equity in Nextpoint, Triursus, and Xios. The anti-PD-L1 antibody BMS-936559 and the anti-TIGIT antibody BMS-g86207-Ab were given by Bristol-Myers Squibb. C.T. serves as a consultant and has received honoraria from Merck, Gilead, G.S.K., AstraZeneca and Medicago. None of aforementioned companies had implications in the design and interpretation of the experiments performed in this manuscript.
(Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)