Chronic HIV-1 infection induces the depletion and functional impairment of group-3 innate lymphoid cells through plasmacytoid dendritic cells and type I interferon

Abstract

Abstract Group 3 innate lymphoid cells (ILC3s) play a key role in promoting antibody production and gut inflammation and immunity; however, their characteristics and relevant regulatory mechanisms in chronic HIV-1 infection are poorly understood partially due to the lack of a robust model. We, here, reported that functional ILC3 cells are developed in all lymphoid organs in humanized mice with similar phenotypes to human counterparts. Importantly, chronic HIV-1 infection activated these tissue-resident ILC3 cells, and subsequently depleted them and preferentially impaired their IL-17a and IL-22 production in vivo of humanized mice, while anti-viral therapy efficiently reversed this alteration. HIV-1-induced depletion of ILC3s and their functional impairment could also be largely recovered by the depletion of plasmacytoid dendritic cells (pDCs) or in vivo of humanized mice and by the blockade of both interferon (IFN)-I and CD95/Fas pathway in vitro. Blockade of IFN-I also recovered IL-17a and IL-22 production in vivo of humanized mice with chronic HIV-1 infection. Additionally, we determined that HIV-1 infection induces CD95 expression on ILC3s via a pDC- and IFN-I–dependent mechanism that sensitizes ILC3s to undergo CD95/FasL-mediated apoptosis. Finally, ILC3 depletion was found to be associated with loss of gut mucosa barrier in HIV-1-infected patients. Thus, we conclude that chronic HIV-1 infection depletes ILC3s through pDC activation, induction of IFN-I, and CD95-mediated apoptosis.