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

EBioMedicine. 2022 Oct:84:104254. doi: 10.1016/j.ebiom.2022.104254. Epub 2022 Sep 20.

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 TFH, TH1, and TH17/TH22 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 TH1- and TH17/TH22-, but not TFH-related functions, increased. Cells co-expressing TH1 and TFH 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.

Keywords: CD4+ T cell subsets; HIV-specific CD4+ T cells; Immune checkpoint blockade; PD-1; T cell dysfunction; TOX.

MeSH terms

  • 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

Substances

  • B7-H1 Antigen
  • Cytokines
  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor
  • Receptors, Chemokine
  • Receptors, Immunologic
  • Transcription Factors
  • RNA