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

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-gamma, 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-1 beta. Mechanistically, IL-1 beta 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. Anti-retroviral treatment does not fully resolve mucosal dysfunction and systemic inflammation in HIV infected individuals. Authors show here that an unusual population of regulatory T cells, distinguished by Amphiregulin expression and the incapability to suppress CD4 T cells might contribute to disrupted oral immune protection in HIV patients.