Restricting nonclassical MHC genes coevolve with TRAV genes used by innate-like T cells in mammals

Abstract

Whereas major histocompatibility class-1 (MH1) proteins present peptides to T cells displaying a large T-cell receptor (TR) repertoire, MH1Like proteins, such as CD1D and MR1, present glycolipids and microbial riboflavin precursor derivatives, respectively, to T cells expressing invariant TR-α (iTRA) chains. The groove of such MH1Like, as well as iTRA chains used by mucosal-associated invariant T (MAIT) and natural killer T (NKT) cells, respectively, may result from a coevolution under particular selection pressures. Herein, we investigated the evolutionary patterns of the iTRA of MAIT and NKT cells and restricting MH1Like proteins: MR1 appeared 170 Mya and is highly conserved across mammals, evolving more slowly than other MH1Like. It has been pseudogenized or independently lost three times in carnivores, the armadillo, and lagomorphs. The corresponding TRAV1 gene also evolved slowly and harbors highly conserved complementarity determining regions 1 and 2. TRAV1 is absent exclusively from species in which MR1 is lacking, suggesting that its loss released the purifying selection on MR1. In the rabbit, which has very few NKT and no MAIT cells, a previously unrecognized iTRA was identified by sequencing leukocyte RNA. This iTRA uses TRAV41, which is highly conserved across several groups of mammals. A rabbit MH1Like gene was found that appeared with mammals and is highly conserved. It was independently lost in a few groups in which MR1 is present, like primates and Muridae, illustrating compensatory emergences of new MH1Like/Invariant T-cell combinations during evolution. Deciphering their role is warranted to search similar effector functions in humans.MHC | TCR | MAIT | evolution | mammals

Targeting Innate-Like T Cells in Tuberculosis

“…The invariant rearrangement of V and J gene fragments possibly occurs upon the stimulation of structurally conserved metabolites available prior to the infection of microbial pathogens. These semi-invariant TCRs are much more “popular” during the development and common in human populations than are the public TCRs (27, 150, 151). In addition to the public TCRs from conventional T cells, MAIT, NKT, GEM, and LDN5-like T cells express semi-invariant TCRs (Table 1).…”

Donor-unrestricted T cells in the human CD1 system

“…Thus, the concept of MHC-restricted TCRs is invoked in the particular situation of shared antigen exposure and matched MHC genes, which is not the usual setting of T cell activation in disease. In contrast, the V and J rearrangements that define NKT and MAIT TCRα chains are conserved broadly across most humans or mice, based on their recognition of a universally expressed antigen-presenting molecule (Porcelli et al 1993; Tilloy et al 1999; Huang et al 2005; Van Rhijn et al 2015a; Van Rhijn and Moody 2015; Boudinot et al 2016). These invariant TCRs are much more public than any MHC-restricted TCR and can be thought of as universal in a species.…”

MAIT cells: an historical and evolutionary perspective

“…In silico analysis indicates that MR1 is not an archaic MHC class I molecule, but appeared in the direct ancestors of mammals. Indeed, MR1 is present in marsupials and eutherians but, contrary to classical MHC molecules, not in reptiles or birds . MR1 is strikingly conserved in mammals with signs of purifying selection .…”

“…These features are related to a unique development pathway in which selection on CD4 + CD8 + double positive (DP) thymocytes leads to the expression of the transcription factors PLZF and, among others, ROR γ t and/or T‐bet . Another characteristic of the two prototypic preset T‐cell subsets is the strong evolutionary conservation of their T‐cell receptors (TCR), TRAV10/11‐TRAJ18 and TRAV1.2‐TRAJ33/20/12, and restricting elements, CD1d and MR1 for NKT and MAIT cells, respectively . .…”