Arming of MAIT Cell Cytolytic Antimicrobial Activity Is Induced by IL-7 and Defective in HIV-1 Infection

Mucosa-associated invariant T (MAIT) cells represent a large innate-like evolutionarily conserved antimicrobial T-cell subset in humans. MAIT cells recognize microbial riboflavin metabolites from a range of microbes presented by MR1 molecules. MAIT cells are impaired in several chronic diseases including HIV-1 infection, where they show signs of exhaustion and decline numerically. Here, we examined the broader effector functions of MAIT cells in this context and strategies to rescue their functions. Residual MAIT cells from HIV-infected patients displayed aberrant baseline levels of cytolytic proteins, and failed to mobilize cytolytic molecules in response to bacterial antigen. In particular, the induction of granzyme B (GrzB) expression was profoundly defective. The functionally impaired MAIT cell population exhibited abnormal T-bet and Eomes expression patterns that correlated with the deficiency in cytotoxic capacity and cytokine production. Effective antiretroviral therapy (ART) did not fully restore these aberrations. Interestingly, IL-7 was capable of arming resting MAIT cells from healthy donors into cytotoxic GrzB+ effector T cells capable of killing bacteria-infected cells and producing high levels of pro-inflammatory cytokines in an MR1-dependent fashion. Furthermore, IL-7 treatment enhanced the sensitivity of MAIT cells to detect low levels of bacteria. In HIV-infected patients, plasma IL-7 levels were positively correlated with MAIT cell numbers and function, and IL-7 treatment in vitro significantly restored MAIT cell effector functions even in the absence of ART. These results indicate that the cytolytic capacity in MAIT cells is severely defective in HIV-1 infected patients, and that the broad-based functional defect in these cells is associated with deficiency in critical transcription factors. Furthermore, IL-7 induces the arming of effector functions and enhances the sensitivity of MAIT cells, and may be considered in immunotherapeutic approaches to restore MAIT cells.
Author Summary The mucosa-associated invariant T (MAIT) cells recognize antigens that are byproducts of the riboflavin biosynthesis pathway shared by many microbes. These antigens are presented by the MHC class I-like MR1 molecules and trigger rapid activation of MAIT cells in an innate-like fashion with deployment of effector mechanisms including cytokine production and cytolysis. Here, we investigated the MAIT cell response to bacteria in humans infected with HIV-1, and possible means to restore functionality to these cells. MAIT cell dysfunction in HIV-infected patients included an inability to express components of the cytolytic effector machinery. Impairment of the MAIT cell population involved the loss of expression of the transcription factors T-bet and Eomes. Interestingly, IL-7 had strong effects on MAIT cells, including the antigen-independent arming of cytolytic function and enhanced sensitivity for low levels of bacteria. In HIV-infected patients, plasma IL-7 levels were positively associated with the size of the MAIT cell population, and IL-7 could rescue their function. These findings indicate that MAIT cell impairment in HIV-1 infection is broad-based, includes loss of critical transcription factors, and loss of cytolytic function. Furthermore, the data support the notion that IL-7 is a strong candidate for immunotherapy in diseases associated with MAIT cell loss.