Diversification of CD1 Molecules Shapes Lipid Antigen Selectivity

Abstract

Molecular studies of host-pathogen evolution have largely focused on the consequences of variation at protein-protein interaction surfaces. The potential for other microbe-associated macromolecules to promote arms race dynamics with host factors remains unclear. The cluster of differentiation 1 (CD1) family of vertebrate cell surface receptors plays a crucial role in adaptive immunity through binding and presentation of lipid antigens to T-cells. Although CD1 proteins present a variety of endogenous and microbial lipids to various T-cell types, they are less diverse within vertebrate populations than the related major histocompatibility complex (MHC) molecules. We discovered that CD1 genes exhibit a high level of divergence between simian primate species, altering predicted lipid binding properties and T-cell receptor (TCR) interactions. These findings suggest that lipid-protein conflicts have shaped CD1 genetic variation during primate evolution. Consistent with this hypothesis, multiple primate CD1 family proteins exhibit signatures of repeated positive selection at surfaces impacting antigen presentation, binding pocket morphology, and TCR accessibility. Using a molecular modeling approach, we observe that inter-species variation as well as single mutations at rapidly-evolving sites in CD1a drastically alter predicted lipid binding and structural features of the T-cell recognition surface. We further show that alterations in both endogenous and microbial lipid binding affinities influence the ability of CD1a to undergo antigen swapping required for T-cell activation. Together these findings establish lipid-protein interactions as a critical force of host-pathogen conflict and inform potential strategies for lipid-based vaccine development.

CD1b glycoprotein, a crucial marker of thymocyte development during T cell maturation in cynomolgus monkeys

“…Although we did not fully define the role of CD1b expression by thymocytes in this study, it is possible that CD1b molecules play a role in development of T cell subsets that recognize nonprotein antigens such as lipids, glycolipids, and lipopeptides presented by group 1 CD1 molecules (CD1a, CD1b, and CD1c) 37 , 38 . Therefore, CD1b molecules may promote development of various T cell lineages that recognize lipid antigens through interactions between thymocytes.…”

The repertoire of protein-sulfatide interactions reveal distinct modes of sulfatide recognition

“…The consensus structural data indicates that it is likely that the side chain of an arginine, and in some cases lysine, makes electrostatic contact with the sulfate moiety ( Zajonc et al, 2003 ; Wang et al, 2006 ; Samygina et al, 2011 ; Stax et al, 2017 ; Song et al, 2020 ). It is possible that a nearby tyrosine residue plays a critical role in this interaction, but it is unlikely that it provides the specificity as observed for the wide range of the α-synuclein ( Fantini and Yahi, 2011 ) and CD1a ( Paterson et al, 2021 ) sphingolipid interactions. Other sulfatide-binding proteins primarily contact the ceramide region with a specific fatty acid chain length, and degree of unsaturation and hydroxylation.…”

Dynamic evolution of bacterial ligand recognition by formyl peptide receptors

“…Orthologous FPR gene regions in primates have previously demonstrated evidence of accelerated evolution in promoters and other regions (Yang 2014) as well as heightened occurrences of single nucleotide polymorphisms (Harris 2020). Many other immune system related proteins including Toll-like receptors (TLRs), TRIM proteins, major histocompatibility complex (MHC) family genes, and transferrins have been subject to repeated positive selection during mammalian evolution (Brunette 2012.;McLaughlin and Malik 2017;Daugherty and Malik 2012;Barber and Elde 2014;Aleru and Barber 2020;Paterson 2021;Sawyer 2005. ; van der Lee 2017.; Hughes and Piontkivska 2008;Hughes and Nei 1990).…”