Share this article on:

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

Sandberg, Johan K.a,b; Dias, Joanaa; Shacklett, Barbara L.c; Leeansyah, Edwina


In this article of issue 16, 2013 , the title should read, “Will loss of your MAITs weaken your HAART?”

AIDS. 28(1):147, January 2nd, 2014.

doi: 10.1097/QAD.0b013e3283620726

aCenter for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge

bCenter for HIV Research, Karolinska Institutet, Stockholm, Sweden

cDepartment of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, California, USA.

Correspondence to Johan K. Sandberg, PhD, Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, F59, 14186 Stockholm, Sweden. E-mail:

Received 19 March, 2013

Revised 4 April, 2013

Accepted 5 April, 2013

Back to Top | Article Outline


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.

Back to Top | Article Outline

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

Fig. 1

Fig. 2

Fig. 2

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

Fig. 3

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].

Back to Top | Article Outline

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.

Back to Top | Article Outline

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.

Back to Top | Article Outline

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.

Back to Top | Article Outline


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.

Back to Top | Article Outline

Conflicts of interest

The authors report no conflict of interest.

Back to Top | Article Outline


1. Le Bourhis L, Guerri L, Dusseaux M, Martin E, Soudais C, Lantz O. Mucosal-associated invariant T cells: unconventional development and function. Trends Immunol 2011; 32:212–218.
2. Martin E, Treiner E, Duban L, Guerri L, Laude H, Toly C, et al. Stepwise development of MAIT cells in mouse and human. PLoS Biol 2009; 7:e54.
3. Walker LJ, Kang YH, Smith MO, Tharmalingham H, Ramamurthy N, Fleming VM, et al. Human MAIT and CD8alphaalpha cells develop from a pool of type-17 precommitted CD8+ T cells. Blood 2012; 119:422–433.
4. Dusseaux M, Martin E, Serriari N, Peguillet I, Premel V, Louis D, et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 2011; 117:1250–1259.
5. Treiner E, Duban L, Bahram S, Radosavljevic M, Wanner V, Tilloy F, et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 2003; 422:164–169.
6. Huang S, Martin E, Kim S, Yu L, Soudais C, Fremont DH, et al. MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution. Proc Natl Acad Sci U S A 2009; 106:8290–8295.
7. Tsukamoto K, Deakin JE, Graves JA, Hashimoto K. Exceptionally high conservation of the MHC class I-related gene, MR1, among mammals. Immunogenetics 2013; 65:115–124.
8. Kjer-Nielsen L, Patel O, Corbett AJ, Le Nours J, Meehan B, Liu L, et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 2012; 491:717–723.
9. Leeansyah E, Ganesh A, Quigley MF, Sonnerborg A, Andersson J, Hunt PW, et al. Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection. Blood 2013; 121:1124–1135.
10. Cosgrove C, Ussher JE, Rauch A, Gartner K, Kurioka A, Huhn MH, et al. Early and nonreversible decrease of CD161++/MAIT cells in HIV infection. Blood 2013; 121:951–961.
11. Le Bourhis L, Martin E, Peguillet I, Guihot A, Froux N, Core M, et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol 2010; 11:701–708.
12. Leeansyah E, Malone DF, Anthony DD, Sandberg JK. Soluble biomarkers of HIV transmission, disease progression and comorbidities. Curr Opin HIV AIDS 2013; 8:117–124.
13. Schwartz O, Marechal V, Le Gall S, Lemonnier F, Heard JM. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat Med 1996; 2:338–342.
14. Chen N, McCarthy C, Drakesmith H, Li D, Cerundolo V, McMichael AJ, et al. HIV-1 down-regulates the expression of CD1d via Nef. Eur J Immunol 2006; 36:278–286.
15. Moll M, Andersson SK, Smed-Sorensen A, Sandberg JK. Inhibition of lipid antigen presentation in dendritic cells by HIV-1 Vpu interference with CD1d recycling from endosomal compartments. Blood 2010; 116:1876–1884.
16. Guillot-Delost M, Le Gouvello S, Mesel-Lemoine M, Cherai M, Baillou C, Simon A, et al. Human CD90 identifies Th17/Tc17 T cell subsets that are depleted in HIV-infected patients. J Immunol 2012; 188:981–991.
17. Gaardbo JC, Hartling HJ, Thorsteinsson K, Ullum H, Nielsen SD. CD3+CD8+CD161high Tc17 cells are depleted in HIV-infection. AIDS 2013; 27:659–662.
18. Kim CJ, Nazli A, Rojas OL, Chege D, Alidina Z, Huibner S, et al. A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis. Mucosal Immunol 2012; 5:670–680.
19. Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, Deeks SG. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis 2003; 187:1534–1543.
20. Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, Rodriguez B, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 2009; 199:1177–1185.
21. Fernandez S, Tanaskovic S, Helbig K, Rajasuriar R, Kramski M, Murray JM, et al. CD4+ T-cell deficiency in HIV patients responding to antiretroviral therapy is associated with increased expression of interferon-stimulated genes in CD4+ T cells. J Infect Dis 2011; 204:1927–1935.
22. Moll M, Snyder-Cappione J, Spotts G, Hecht FM, Sandberg JK, Nixon DF. Expansion of CD1d-restricted NKT cells in patients with primary HIV-1 infection treated with interleukin-2. Blood 2006; 107:3081–3083.

antiretroviral therapy; HIV-1; interleukin-17; MR1; mucosa-associated invariant T cells

© 2013 Lippincott Williams & Wilkins, Inc.