Oral immune dysfunction is associated with the expansion of FOXP3⁺PD-1⁺Amphiregulin⁺ T cells during HIV infection.

Abstract

Residual systemic inflammation and mucosal immune dysfunction persist in people living with HIV, despite treatment with combined anti-retroviral therapy, but the underlying immune mechanisms are poorly understood. Here we report that the altered immune landscape of the oral mucosa of HIV-positive patients on therapy involves increased TLR and inflammasome signaling, localized CD4⁺ T cell hyperactivation, and, counterintuitively, enrichment of FOXP3⁺ T cells. HIV infection of oral tonsil cultures in vitro causes an increase in FOXP3⁺ T cells expressing PD-1, IFN-γ, Amphiregulin and IL-10. These cells persist even in the presence of anti-retroviral drugs, and further expand when stimulated by TLR2 ligands and IL-1β. Mechanistically, IL-1β upregulates PD-1 expression via AKT signaling, and PD-1 stabilizes FOXP3 and Amphiregulin through a mechanism involving asparaginyl endopeptidase, resulting in FOXP3⁺ cells that are incapable of suppressing CD4⁺ T cells in vitro. The FOXP3⁺ T cells that are abundant in HIV-positive patients are phenotypically similar to the in vitro cultured, HIV-responsive FOXP3⁺ T cells, and their presence strongly correlates with CD4⁺ T cell hyper-activation. This suggests that FOXP3⁺ T cell dysregulation might play a role in the mucosal immune dysfunction of HIV patients on therapy.