Homology Between an Alloantigen and a Self MHC Allele Calibrates the Avidity of the Alloreactive T Cell Repertoire Independent of TCR Affinity

Abstract

The self-restricted T cell repertoire exhibits a high frequency of alloreactivity. Because these alloreactive T cells are derived from the pool of cells selected on several different self MHC alleles, it is unknown how development of the alloantigenic repertoire is influenced by homology between a self MHC allele and an alloantigen. To address this, we used the 2C transgenic TCR that is selected by Kb, is alloreactive for Ld, and cross-reacts with Lq. Lq is highly homologous to Ld and binds several of the same peptide ligands, including p2Ca, the peptide recognized by 2C. We find that Ld/p2Ca is a high avidity agonist ligand, whereas Lq/p2Ca is a low avidity agonist ligand for 2C T cells. When mice transgenic for the 2C TCR are bred to Lq-expressing mice, 2C+ T cells develop; however, they express lower levels of either the 2C TCR or CD8 and require a higher Ld/p2Ca ligand density to be activated than 2C+ T cells selected by Kb. Furthermore, the 2C T cells selected in the presence of Lq fail to detect Lq/p2Ca complexes even at high ligand density. Thus, despite possessing the identical TCR, there is a functional avidity difference between 2C+ T cells selected in the presence of Lq vs Kb. These data provide evidence that homology between the selecting ligand and an alloantigen can influence the avidity of the T cell repertoire for the alloantigen, and suggest that thymic selection can fine tune T cell avidity independent of intrinsic TCR affinity.

The Same Major Histocompatibility Complex Polymorphism Involved in Control of HIV Influences Peptide Binding in the Mouse H-2Ld System

“…Although much has been learned about aspects of the HLA-B alleles in terms of disease association and structure, little attention has been paid to a mouse MHC system (H2-L) that has structural and genetic similarities to the HLA-B system, and could inform studies of HIV immunity. Notably, these genetic similarities include two alleles, L d and L q , which express Trp 97 and Arg 97 polymorphisms, respectively (42). Furthermore, the Arg 97 substitution has been shown, by a completely independent approach, to stabilize the peptide⅐H-2L d complex (33).…”

The Ig-Like Domain of Tapasin Influences Intermolecular Interactions

“…The 2C clone also recognizes a nonamer variant of p2Ca, called QL9 (QLSPFPFDL) (44). The p2Ca peptide has a very low affinity for L d (45)(46)(47)(48)(49), although the QL9 peptide has higher affinity for L d (47,48). Recognition of L d by the 2C CTL clone was depressed by the presence of human tapasin H334F/H335Y in 721.220 cells relative to wild-type tapasin (Fig.…”

Role of MHC Restriction in Allogeneic Immune Responses to Cancer

“…Thymic positive selection and the mode of alloreactivity induction are the major independent factors determining the patterns of alloantigen recognition [6]. Homology between the selecting ligand and an alloantigen can influence the avidity of the T cell repertoire for the alloantigen [7]. The structural basis for the crossreactivity between different MHC alleles is the similarity in amino acid sequence of that part of the molecule predicted to make contact with the T cell receptor [TcR] [8].…”