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Homology Between an Alloantigen and a Self MHC Allele Calibrates the Avidity of the Alloreactive T Cell Repertoire Independent of TCR Affinity¹

Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110

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 K^b, is alloreactive for L^d, and cross-reacts with L^q. L^q is highly homologous to L^d and binds several of the same peptide ligands, including p2Ca, the peptide recognized by 2C. We find that L^d/p2Ca is a high avidity agonist ligand, whereas L^q/p2Ca is a low avidity agonist ligand for 2C T cells. When mice transgenic for the 2C TCR are bred to L^q-expressing mice, 2C⁺ T cells develop; however, they express lower levels of either the 2C TCR or CD8 and require a higher L^d/p2Ca ligand density to be activated than 2C⁺ T cells selected by K^b. Furthermore, the 2C T cells selected in the presence of L^q fail to detect L^q/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 L^q vs K^b. 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.

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