The structure and amino acid diversity of the T-cell receptor (TCR) similar in nature to that of Fab portions of antibodies would suggest these proteins have a nearly infinite capacity to recognize antigen. TCRs of mouse and human. By presenting this broad view of TCR sequence structure domain organization and function we seek to explore how this receptor has evolved across time and been N3PT selected for alternative antigen-recognition capabilities in divergent lineages. genus which includes horses zebras and asses have the largest known family of CD1 genes with 13 genes total showing 60-83% identity to their human counterparts (48). Seven isoforms were classified as CD1a two as CD1b one as CD1c one as CD1d and two as CD1e (48) (Table 1). The largest differences between horse and human CD1 are found in the α1 and α2 helices which are principally responsible for lipid binding and TCR contacts (48). Table 1 Ruminants including cows also express multiple CD1 molecules including CD1a CD1e and three CD1b isoforms with differences in their binding groove and cytoplasmic tails (Table 1). Although these species were originally thought to lack CD1d due to absence of a functional start codon (49) it was later found that cows do in fact express cell surface CD1d (50) (Table 1). Bovine CD1d is able to bind to glycosphingolipids with short fatty acid chain lengths including C12-di-sulfatide C16-αGalCer and C18 but not longer C24 fatty acids (50 51 The crystal structure of bovine CD1d in complex with C16-αGalCer confirmed that it has a flexible binding groove and plasticity in the A′ pocket due to changes in the conserved Trp40 residue (51). The A′ pocket was also considerably shorter than mouse and human CD1d due to interaction between Trp166 and Thr100 inside the pocket explaining the inability of bovine CD1d to bind fatty acids with longer chains (51). The crystal structure of another bovine CD1 isoform CD1b3 also showed variations in the binding pocket compared to human CD1b. The T′ tunnel in this structure is closed due to the presence of valine instead of glycine at position 98 suggesting that like CD1d CD1b3 might bind a skewed set of lipids (52). Additionally there is a roof over the N3PT F′ pocket which prevents presentation of alkyl chains toward the presumed TCR interface as is seen in human CD1b (21 52 It is unclear if the other CD1b isoforms may have more ‘normal’ human-like binding pockets. It is reasonable to assume that diverse microbial and self-lipids would be present in different species leading to adaptations in the binding pockets of CD1 in both horses and ruminants. Unlike most placental mammals (besides rodents) which have multiple CD1 genes marsupials only possess one CD1 isoform CD1. Marsupial CD1 is functionally expressed in some species including bandicoot (to agonist lipid ligands without prior need for clonal expansion influencing a nascent immune response with their copious cytokine production. With regards to infection certain pathogen-derived α-linked glycolipids can stimulate NKT cells (74-76) and again biochemical and structural studies have validated high affinity TCR-lipid-CD1d interactions and typical iNKT TCR docking modes (77 78 The ability of iNKT Rabbit Polyclonal to FANCD2. TCRs to recognize certain glycolipids from gram-negative bacterial lacking the potent innate-immune stimulatory lipopolysaccharide suggests they may have evolved as a bridge between the innate and adaptive immune systems perhaps in a similar role as the Toll-like receptors N3PT (TLRs) upon various innate immune system cells. Yet unlike the innate immune receptors iNKT TCRs are inherently autoreactive blurring the lines for their role as a potential innate-like pathogen sensor. Reductionist studies in the murine system have painted a landscape of distinct iNKT cell functions yet a unified model of their specific roles in human health is currently still being unraveled (79). iNKT cell populations in diverse vertebrate species Despite the conservation of CD1 and especially CD1d in many species the role of T-cell-specific responses to these molecules outside of mice and humans is not entirely clear. iNKT-like cells using similar Vα and Jα segments to human and mouse iNKT cells have also been identified in canines based on binding to CD1d/αGalCer (80) and a similar TCR α chain N3PT to TRAV10V/Vα24 has been described in horses pigs cows sheep and rabbits (81) (Table 1). However only horses and pigs were found to contain sequences homologous to the canonical CDR3 regions of human and mouse iNKT cells (81). These species all express CD1d so it is possible that they still have functional CD1-restricted iNKT cells but with.