Functional role of mucosal-associated invariant T cells in HIV infection

Abstract

MAIT cells represent an evolutionarily conserved, MR1-restricted, innate-like cell subset that express high levels of CD161; have a canonical semi-invariant TCR iVα7.2; and may have an important role in mucosal immunity against various bacterial and fungal pathogens. Mature MAIT cells are CD161(hi)PLZF(hi)IL-18Rα(+)iVα7.2(+)γδ-CD3(+)CD8(+) T cells and occur in the peripheral blood, liver, and mucosa of humans. MAIT cells are activated by a metabolic precursor of riboflavin synthesis presented by MR1 and, therefore, respond to many bacteria and some fungi. Despite their broad antibacterial properties, their functional role in persistent viral infections is poorly understood. Although there is an increasing line of evidence portraying the depletion of MAIT cells in HIV disease, the magnitude and the potential mechanisms underlying such depletion remain unclear. Recent studies suggest that MAIT cells are vulnerable to immune exhaustion as a consequence of HIV and hepatitis C virus infections and HIV/tuberculosis coinfections. HIV infection also appears to cause functional depletion of MAIT cells resulting from abnormal expression of T-bet and EOMES, and effective ART is unable to completely salvage functional MAIT cell loss. Depletion and exhaustion of peripheral MAIT cells may affect mucosal immunity and could increase susceptibility to opportunistic infections during HIV infection. Here, we review some of the important mechanisms associated with depletion and functional loss of MAIT cells and also suggest potential immunotherapeutic strategies to restore MAIT cell functions, including the use of IL-7 to restore effector functions in HIV disease.

Keywords: CD8+ T cells; PD-1; TCR iVα7.2; cytotoxicity; exhaustion.

Figure 1

Mechanisms involved in the activation of MAIT cells. MAIT cells express a semi‐invariant TCR‐α chain, including an iVα7.2 segment combined with restricted Jα segments (Jα33, Jα12, or Jα20) and limited Vβ repertoires in humans. In addition, human MAIT cells express high levels of CD161, IL‐18Rα, the transcription factor PLZF, and the chemokine receptors CCR5, CCR6, and CXCR6. Mature MAIT cells are defined as CD161^hiPLZF^hiIL‐18Rα⁺iVα7.2⁺γδ⁻CD3⁺ lymphocytes. MAIT cells recognize unstable pyrimidine intermediates, formed by the nonenzymatic condensation of 5‐A‐RU, an early intermediate of vitamin B₂ (riboflavin) synthesis, with glyoxal or MeG, derived from other metabolic pathways, presented by the highly evolutionarily conserved MR1 on APCs. This interaction leads to activation of the MAIT cell. After activation, MAIT cells can promptly kill infected cells, inhibit intracellular microbial growth, and produce proinflammatory cytokines, including IFN‐γ, TNF‐α, and IL‐17. It is noteworthy that MAIT cells can also be activated via exposure to the cytokines IL‐12 and IL‐18 in a TCR‐independent manner. MAIT cells also express high levels of NKG2D, which has a role as a cytotoxicity coreceptor.

Figure 2

Proposed mechanism illustrating the crosstalk of APCs with MAIT cells across mucosal tissues in HIV infection. (A) Microbial translocation into the gut mucosa could release bacterial‐derived vitamin B metabolites that can activate MAIT cells in an MR1‐dependent manner. (B) APCs could also be exposed to HIV, which in turn can activate MAIT cells in an MR1‐independent fashion. (C) MAIT cells can also be activated through both MR1‐dependent and ‐independent pathways in which APCs are exposed not only to HIV but also to gut bacteria. (Bacteria can also activate the MR1‐independent pathway via stimulation of IL‐12 and IL‐18 secretion, and the type of TLR associated depends on the APC involved.) (D) Aberrant inflammatory responses can affect the mucosal epithelial integrity. Given that MAIT cells are known to produce IFN‐γ and TNF‐α along the mucosa by MR1‐dependent (A and B) and MR1‐independent (C) pathways of MAIT cell activation, IFN‐γ has been reported to induce cellular internalization of proteins associated with tight junctions, resulting in decreased transepithelial resistance in the gut epithelium [60, 61]. Furthermore, TNF‐α has also been reported to induce mucosal epithelial cell death resulting from tight‐junction changes [60, 61], leading to inflammation and mucosal damage (D).

Figure 3

Proposed mechanism of MAIT cell restitution in the colon and blood following the initiation of ART. MAIT cells are lost from the colon during HIV infection [43], although the rate of MAIT loss may be markedly slower than it is in blood MAIT [42]. MAIT cell frequency is reconstituted in the colon following the initiation of ART [43]. Reconstitution may occur because of decreased mucosal inflammation and may be due to recruitment of MAIT cells from other compartments, such as the blood, or from local proliferation. MAIT‐cell reconstitution after initiation of ART is slower in blood than it is in the colon.

Figure 4

Phenotype of exhausted MAIT cells. PD‐1 is linked to exhaustion of MAIT cells in HIV, HIV/TB coinfection, and chronic HCV disease. Both exhausted and activated MAIT cells also down‐regulate CD161. The role of other coinhibitory molecules, such as TIM‐3 and CD244, and immune activation molecules, such as HLA‐DR, CD38, CD69, and CD57, are currently being investigated. Abnormal expression patterns of the transcription factors T‐bet and EOMES are believed to result in insufficiency of cytotoxic functions and cytokine production by MAIT cells.

Figure 5

Proposed mechanism of long‐term activation of MAIT cells and their subsequent exhaustion during HIV infection. (A) HIV stimulates MAIT cells through the MR1‐independent pathway in which viral molecular patterns (e.g., ssRNA) are detected by pattern recognition receptors (e.g., TLR8) on APCs. (B) Microbial translocation results in MAIT‐cell activation through APCs via the MR1‐dependent pathway. (C) Long‐term activation of MAIT cells by MR1‐dependent and ‐independent pathways. (D) Decreased expression of transcription factors in MAIT cells occurs. (E) Increased expression of coinhibitory molecules and immunosenescence markers in MAIT cells also occurs. (F) Functional impairment of MAIT cells is caused by decreased production of IFN‐γ, TNF‐α, and IL‐17 as well as granzyme A/B and perforin.