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

N. Bhaskaran, E. Schneider, F. Faddoul, A. Paes da Silva, R. Asaad, A. Talla, N. Greenspan, A. D. Levine, D. McDonald, J. Karn, M. M. Lederman and P. Pandiyan ()
Additional contact information
N. Bhaskaran: Case Western Reserve University
E. Schneider: Case Western Reserve University
F. Faddoul: Case Western Reserve University
A. Paes da Silva: Case Western Reserve University
R. Asaad: Division of Infectious Diseases & HIV Medicine
A. Talla: Case Western Reserve University
N. Greenspan: Case Western Reserve University
A. D. Levine: Case Western Reserve University
D. McDonald: NIAID, NIH
J. Karn: Case Western Reserve University
M. M. Lederman: Division of Infectious Diseases & HIV Medicine
P. Pandiyan: Case Western Reserve University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25340-w

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