Acquisition of innate-like microbial reactivity in mucosal tissues during human fetal MAIT-cell development

Abstract

Innate-like, evolutionarily conserved MR1-restricted mucosa-associated invariant T (MAIT) cells represent a large antimicrobial T-cell subset in humans. Here, we investigate the development of these cells in second trimester human fetal tissues. MAIT cells are rare and immature in the fetal thymus, spleen and mesenteric lymph nodes. In contrast, mature IL-18Rα+ CD8αα MAIT cells are enriched in the fetal small intestine, liver and lung. Independently of localization, MAIT cells express CD127 and Ki67 in vivo and readily proliferate in response to Escherichia coli in vitro. Maturation is accompanied by the gradual post-thymic acquisition of the PLZF transcription factor and the ability to produce IFNγ and IL-22 in response to bacteria in mucosa. Thus, MAIT cells acquire innate-like antimicrobial responsiveness in mucosa before exposure to environmental microbes and the commensal microflora. Establishment of this arm of immunity before birth may help protect the newborn from a range of pathogenic microbes.

Harnessing the antibacterial and immunological properties of mucosal-associated invariant T cells in the development of novel oral vaccines against enteric infections

“…As mucosal tissues represent the entry sites of the majority of pathogens, the accumulation of MAIT cells in these tissues along with their homing abilities to mucosal tissues confers them with an additional antibacterial advantage. Although human MAIT cell development has recently been suggested to be distinct from the previously proposed mouse MAIT cell process [47], pre-natal MAIT cells have been shown to display antimicrobial responsiveness, therefore, this is consistent with their previously described antibacterial function. Thus, MAIT cells may provide early protection to newborns from bacterial infections, during a time where the adaptive immune system is immature.…”

“…Low numbers of DP and CD4 + MAIT cells have also been reported [12,43,46]. In healthy adults, circulating MAIT cells are in a hypoproliferative state [47,48]. However, this hypoproliferative phenotype can be lost in some inflammatory disease states, for example in inflammatory bowel disease, where there is an increase in circulating activated MAIT cells expressing, Ki67, a marker of cell cycling [48].…”

“…However, following stimulation with anti-CD3/CD28, only TNFb secretion was increased. Pre-natal human MAIT cells, from the small intestine, liver, and lung, produced moderate amounts of IFNg following stimulation ex vivo with paraformaldehyde fixed bacteria and CD28 [44,47].…”

“…Interestingly, the requirement for direct exposure to commensal microflora does not appear to be the case in humans as prenatal development of mature MAIT cells and their enrichment in the lungs and intestines is seen. This is prior to establishment of intestinal microflora or exposure to environmental bacteria [47]. It is possible, however, that small molecule exogenous ligands from bacteria may be transferred from the mother to the foetus resulting in MAIT cell development before postnatal bacterial colonization.…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…IL18R signalling induces the secretion of IFN γ in response to IL‐12+ IL‐18, compared with their respective ‘dim’ counterparts. CD161++ CD8+ T‐cells are uniformly high in IL‐18R expression regardless of whether they are MAIT cells or non‐MAIT, CD161++ V α 7·2−, cells,14 and this is already pre‐programmed in fetal and cord blood cells 83, 87. Additionally, CD56 bright NK cells are known for their proliferative capacity in response to cytokines;88 for example, liver‐resident CD49a+ NK cells have been found to express high levels of CD25, and were able to proliferate in response to low doses of IL‐2 89.…”