An Invariant T Cell Receptor α Chain Defines a Novel TAP-independent Major Histocompatibility Complex Class Ib–restricted α/β T Cell Subpopulation in Mammals

Abstract

We describe here a new subset of T cells, found in humans, mice, and cattle. These cells bear a canonical T cell receptor (TCR) α chain containing hAV7S2 and AJ33 in humans and the homologous AV19-AJ33 in mice and cattle with a CDR3 of constant length. These T cells are CD4−CD8− double-negative (DN) T cells in the three species and also CD8αα in humans. In humans, their frequency was ∼1/10 in DN, 1/50 in CD8α+, and 1/6,000 in CD4+ lymphocytes, and they display an activated/memory phenotype (CD45RAloCD45RO+). They preferentially use hBV2S1 and hBV13 segments and have an oligoclonal Vβ repertoire suggesting peripheral expansions. These cells were present in major histocompatibility complex (MHC) class II– and transporter associated with antigen processing (TAP)-deficient humans and mice and also in classical MHC class I– and CD1-deficient mice but were absent from β2-microglobulin–deficient mice, indicating their probable selection by a nonclassical MHC class Ib molecule distinct from CD1. The conservation between mammalian species, the abundance, and the unique selection pattern suggest an important role for cells using this novel canonical TCR α chain.

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

“…The MAIT cells were shown early on to be present in the human gut lamina propria,1, 2 to express the gut homing integrin α 4 / β 7 , and have been considered to be preferentially located in mucosal tissue 27. Moreover an important role in gastrointestinal mucosal immunity is suggested by the dependence on commensal gut flora for their development in mice 2, 16.…”

“…Mucosal‐associated invariant T (MAIT) cells are a subset of innate‐like T lymphocytes first described in 1999,1 which are abundant in humans and can rapidly express a range of pro‐inflammatory cytokines. Although MAIT cells express an αβ T‐cell receptor (TCR) they differ from conventional T cells in that this receptor has a limited TCR diversity, mostly comprising a semi‐invariant TCR‐ α chain associated with a limited repertoire of TCR‐ β chains (Box 1).…”

“…Most MAIT cell TCRs comprise a semi‐invariant TCR‐ α chain – usually TRAV1‐2‐TRAJ33 (V α 7.2 − J α 33 in humans, V α 19 − J α 33 in mice),90 although in humans some MAIT cells also use TRAV1‐2‐TRAJ12 or TRAV1‐2‐TRAJ2022) – predominantly associated with the β ‐chains TRBV20 (V β 2) or TRBV6 (V β 13) in humans1 and TRBV19 (V β 6) or TRBV13 (V β 8) in mice 1, 22, 23. These preferential TCR rearrangements arise partly through a process of ‘convergent recombination’91 whereby much of the antigen specificity of MAIT cells is essentially germline‐encoded.…”

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

“…In paraformaldehyde fixed healthy human jejunal tissue biopsies Va7.2 positive cells are located in the LP at the base of the villi, and less commonly in the villus tip, and in the IEL compartment [43]. Numbers of MAITs in wild type mice are far lower than in humans and are mainly confined to the intestinal LP and lymph nodes (they were not detected in the liver, bone marrow or spleen in mice) [10,49]. Although initial research demonstrated significant numbers of MAIT cells at mucosal sites, recently, significant accumulation of MAITs was also revealed in the human liver (up to 45% of hepatic T lymphocytes) [45].…”

“…However, targeting populations of unconventional T cells may represent a highly productive strategy to improve the efficacy of oral vaccines at mucosal surfaces. Mucosal associated invariant T (MAIT) cells are a recently discovered innate populations of unconventional T cells [9,10]. These cells accumulate at mucosal sites, home to mucosal tissue when activated, rapidly produce immunomodulatory cytokines in response to bacterial stimuli, can bridge innate and adaptive immunity, and share common features with the more widely studied invariant Natural Killer T (iNKT) cells, agonists of which have previously been shown to have vaccine adjuvant properties.…”