Oral immune dysfunction is associated with the expansion of FOXP3+PD-1+Amphiregulin+ T cells during HIV infection.
N BhaskaranE SchneiderF FaddoulA Paes da SilvaR AsaadA TallaN GreenspanAlan D LevineD McDonaldJonathan KarnM M LedermanP PandiyanPublished in: Nature communications (2021)
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.
Keyphrases
- hiv positive
- regulatory t cells
- antiretroviral therapy
- end stage renal disease
- men who have sex with men
- ejection fraction
- south africa
- human immunodeficiency virus
- hiv infected
- prognostic factors
- oxidative stress
- inflammatory response
- immune response
- hiv aids
- peritoneal dialysis
- induced apoptosis
- dendritic cells
- hiv testing
- patient reported outcomes
- toll like receptor
- drug delivery
- cell cycle arrest
- cell therapy
- hepatitis c virus
- bone marrow
- nuclear factor
- endothelial cells
- single cell
- ulcerative colitis
- drug induced