Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 8, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI155251
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Funding
- NIH/NIAID [R21AI122380, R37AI141258, R01AI116379]
- NIH/NHLBI/NIDDK/NINDS/NIDA/NIAID grant [UM1AI164562]
- NIH/OD grants [P51OD011132, U42OD011023, P51OD011092, 1S10OD025002-01]
- NIH/NCRR grant [R24RR016988]
- NIH/NCI grants [75N91019D00024, HHSN261200800001E]
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IL-10 in SIV-infected macaques affects Tfh cell differentiation and germinal center formation. IL-10 correlates with LN CD4(+) memory subsets and predicts CD4(+) Tfh cell frequency during ART.
Interleukin-10 (IL-10) is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper (Tfh) cell differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph nodes (LNs) were induced by infection and not normalized with antiretroviral therapy (ART). During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4(+) memory subsets, including Tfh cells, and predicted the frequency of CD4(+) Tfh cells and their cell-associated SIV-DNA content during ART, respectively. In ART-treated rhesus macaques, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and, by extension, LN memory CD4(+) T cells, including Tfh cells and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4(+ )T cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.
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