Abstract
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.
Highlights
Mucosa-associated invariant T (MAIT) cells are a recently described subset of unconventional, innate-like T cells that are highly abundant in mucosal tissues, liver and circulation of healthy humans [1,2,3,4]
We investigated the MAIT cell response to bacteria in humans infected with HIV-1, and possible means to restore functionality to these cells
IL-7 had strong effects on MAIT cells, including the antigen-independent arming of cytolytic function and enhanced sensitivity for low levels of bacteria
Summary
Mucosa-associated invariant T (MAIT) cells are a recently described subset of unconventional, innate-like T cells that are highly abundant in mucosal tissues, liver and circulation of healthy humans [1,2,3,4]. MAIT cells express a semi-invariant T cell receptor (TCR), including Vα7.2 coupled with restricted Jα segments (Jα33, Jα12, or Jα20), and limited Vβ repertoires [5, 6]. Certain innate cytokines, including IL-12 and IL-18, can stimulate MAIT cells to produce IFNγ independently of the MR1-TCR interaction [22, 23]. These findings are strongly supportive of the notion that MAIT cells perform critical functions in the immune system, beyond their role as antimicrobial T cells, at mucosal sites
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