Will loss of your mucosa-associated invariant T cells weaken your HAART?

Introduction Mucosa-associated invariant T (MAIT) cells are a relatively recently described subset of T cells, representing some 2–10% of peripheral blood T cells in healthy donors [1]. They are mostly CD8+, although CD4/CD8 double-negative or CD4+ populations also exist [2,3], and can comprise up to 10–25% of T cells in the liver and at intestinal sites [4]. MAIT cells are CD161hi, characterized by their Vα7.2-containing semi-invariant T-cell receptor, and respond to antigens presented by the evolutionarily conserved major histocompatibility class (MHC) class Ib related protein 1 (MR1) [5–7]. They respond rapidly in an innate-like fashion and with a predominant Th1/Th17 profile [4]. MAIT cells display tropism for mucosal sites with expression of chemokine receptors such as CC chemokine receptor 6 (CCR6), CCR9 and CXC chemokine receptor 6 (CXCR6), and in mucosa, they express the tissue-protective cytokine IL-22 [3,4]. The type of antigens presented by MR1 molecules was long elusive, but recently described to include derivatives of the microbial vitamin B biosynthetic pathway [8]. As components of these pathways are shared by many microbes but not by mammals, they represent good targets of a conserved immune mechanism at mucosal sites wherein such microbes are encountered. In line with this, MAIT cells are emerging as an important component of the healthy mucosal immune system. Irreversible loss of mucosa-associated invariant T cells in HIV-1 infection: how, where and when? Given the characteristics of MAIT cells, it is reasonable to hypothesize a role for these cells in patients who suffer from acquired immunodeficiency and impaired control of microbial infections. Two recent studies investigated the impact of HIV-1 infection on the MAIT cell compartment [9,10]. These studies together indicate that MAIT cells decline numerically in peripheral blood of HIV-1-infected individuals, whereas the loss of these cells appears to be slower in gut-associated lymphoid tissue (Fig. 1). The function of residual MAIT cells is reduced with lower cytokine production in response to Escherichia coli, where in particular IL-17 production is essentially completely lost. Importantly, peripheral blood MAIT cells do not recover significantly in numbers, as patients initiate combination antiretroviral therapy (ART), even when viral load is suppressed to undetectable levels for several years and the CD4 compartment recovers (Fig. 2). Suppression of viremia does however benefit the status of residual MAIT cells, as evidenced by a partial recovery of cytokine production.Fig. 1: Mucosa-associated invariant T-cell loss in HIV-1 infection.MAIT cells are activated, exhausted and persistently depleted in chronic HIV-1 infection. The exact kinetics of MAIT cell loss in blood and mucosa are unknown. MAIT, mucosa-associated invariant T.Fig. 2: The loss of mucosa-associated invariant T cells is not reversed by successful antiretroviral therapy.The function of MAIT cells recovers partly when patients go on ART. The effect of ART on mucosal MAIT cells is so far unknown. ART, antiretroviral therapy; MAIT, mucosa-associated invariant T.Loss of MAIT cells in HIV infection occurs despite that they are predominantly CD8-positive cells and appear to be relatively resistant to direct infection by the virus [10]. The data support a model wherein the MAIT cell compartment is engaged in immune responses and declines as a consequence of persistent activation, exhaustion and apoptosis [9,10]. Notably, however, MAIT cells probably do not respond to viral antigens [11], leaving the open question what the driving force of activation and exhaustion may be. Given what we know about the nature of MR1-presented antigens, it is reasonable to speculate that persistent exposure to bacterial and fungal antigens might drive these changes. Loss of immune control of bacteria and fungi at mucosal surfaces may lead to an enhanced burden on MAIT cells at these sites (Fig. 3). Furthermore, microbial translocation products may also engage MAIT cells not only in the mucosal epithelium and lamina propria but also in the liver. In this context, the paucity of unequivocal markers of microbial translocation is problematic [12]. In fact, the same vitamin B metabolites recognized by MAIT cells may potentially serve as novel microbial translocation markers in plasma.Fig. 3: Hypothetical model of mucosa-associated invariant T-cell recruitment, activation, exhaustion and loss at the mucosal frontlines.According to the exhaustion model of MAIT cell loss, the loss would occur as they are exhausted and consumed at the ‘frontlines’ of exposure to microbes (Fig. 3). Data from matched blood and rectal biopsy material support the possibility that the decline of peripheral blood MAIT cells may in part be driven by recruitment to the intestinal mucosa. Significant loss of MAIT cells in the mucosa may then become more apparent, as their levels in peripheral blood and other nonmucosal sites become depleted. It will be important to investigate mucosal sites other than the rectal mucosa to fully understand these events. Yet, another possibility to consider is that HIV may actively perturb MR1-mediated antigen presentation. This is the case for both classical human leukocyte antigen (HLA) class I molecules and MHC class I-like molecules such as CD1d [13–15]. If similar mechanisms exist to interfere with MR1 pathways, then this may contribute to MAIT cell dysfunction in HIV-1 infection. The exact kinetics of MAIT cell loss in HIV-1-infected patients remains unclear. The study by Cosgrove et al.[10] observed that MAIT cell loss was pronounced already early in infection, whereas a negative correlation between MAIT cell percentage and estimated time since infection was found in our study. This apparent discrepancy may be explained by differences between the cohorts. If our model is correct and MAIT cell exhaustion and loss occurs at mucosal sites, the rate of loss from blood can probably be influenced by the total infectious disease burden and environmental factors. MAIT cells overlap at least partly with the CD8 T-cell population described as Tc17 cells. The Tc17 population express CD161 and have the capacity to produce interleukin (IL)-17. Our data suggest that the majority of these cells are MAIT cells as defined by the expression of the Vα7.2 T-cell receptor (unpublished observations). Interestingly, it was recently reported that Tc17 cells are lost in HIV infection [16,17], in concordance with the observations on MAIT cells [9,10]. Consequences and implications: an argument for early antiretroviral therapy With the data suggesting that MAIT cell numbers do not recover on ART, we have reason to believe that the damage that has been done to this immune cell compartment will persist over time. On the positive side, however, the data suggest that suppression of viremia with effective ART prevents further decay of the MAIT cells. These patterns may have important implications for immune defence against several microbes relevant in HIV immunopathogenesis. For example, both Mycobacterium tuberculosis and Candida albicans are targets of MAIT cell responses [11], and MAIT cells probably make up a substantial fraction of the CD8 T-cell response against these pathogens. Importantly, effective ART allows the residual MAIT cells to regain a relative level of functionality, although not to levels fully comparable to uninfected healthy controls. In this context, the ability of tissue MAIT cells to produce IL-22 may be important, given the recent data suggesting that this cytokine has a protective role in maintenance of mucosal epithelium [18]. The relatively early decay of the MAIT cell compartment thus adds an argument in favour of treating HIV-1 infection as early as possible. When MAIT cells are preserved, they may contribute to a better mucosal immune status and barrier function. Poor recovery of CD4+ cell counts on ART can be associated with remaining elevated immune activation and microbial translocation markers [19–21]. Early treatment and the resulting maintenance of relatively healthy levels of MAIT cells may positively influence the clinical recovery. Can the mucosa-associated invariant T-cell compartment be restored? The persisting defect in MAIT cells in patients on ART suggests that many of the patients treated for HIV-1 infection today have a persistent weakness in the ability to handle bacterial and fungal infections, including opportunistic infections. With this understanding, we should consider ways to restore MAIT cells in vivo by immunotherapeutic intervention. Cytokine treatment overall had limited success in the context of HIV infection. However, another innate-like T-cell subset, the invariant natural killer T (iNKT) cells, was previously shown to expand in vivo in response to IL-2 treatment in combination with effective ART [22]. It may thus be interesting to evaluate the effect of IL-2 therapy on MAIT cells in HIV-1 infected patients. MAIT cells express receptors for both IL-7 and IL-18, suggesting that the prospect of these cytokines in treatment should also be evaluated. A more direct approach is to test the potential of probiotic bacteria in stimulating MAIT cell recovery. Species of Lactobacillus, which are included in many probiotic products, are stimulatory to these cells and may have a positive effect [11]. Other bacteria that are part of the normal commensal gut flora would also be of interest. Stimulation of MAIT cell recovery by such ‘friendly’ microbes would be consistent with the expansion seen during the first year of life when the normal flora is established. Finally, MAIT cells may need both suitable antigens and cytokines to expand, suggesting that a mixed cytokine along with probiotics approach may be a viable way forward. Concluding remarks MAIT cells are part of the CD8 T-cell compartment and their numerical and functional decline in HIV-1 infection was at the first instance unexpected. Their loss is likely to put a significant dent in the human host defence against microbes at mucosal surfaces. The persistence of MAIT cell loss on ART needs to be taken into account when assessing the immunological response to treatment, and when treatment should commence. The importance of this innate-like T-cell subset in HIV-1 infection needs further study, and interventions to restore MAIT cell numbers should be considered. Acknowledgements All authors contributed to the writing of this article. This work was supported by grants from the Swedish Research Council, the Swedish Cancer Foundation, the Stockholm County Council and NIH/NIAID R01-AI057020. E.L. is a Swedish Institute Postdoctoral Fellow. J.D. is supported by a PhD fellowship from the Fundação para a Ciência e a Tecnologia (FCT). J.K.S. is a Senior Research Fellow of the Swedish Research Council. Conflicts of interest The authors report no conflict of interest.