Nonrandom selection of T cell specificities in anti-HLA-DR responses: Sequence motifs of the responder HLA-DR allele influence T cell recruitment

The self-restriction of Ag-specific T cell responses is interpreted as the result of a positive selection of the individual's T cell specificities for their compatibility with self-MHC molecules. If the T cell receptor (TCR) specificities in any given individual have an affinity for syngeneic MHC molecules, it is unclear how they interact with allogeneic MHC structures. To approach this question, we analyzed 123 alloreactive HLA-DR4 Dw4 or Dw 14 specific T cell clones that were generated from responder/stimulator combinations with defined disparities in the HLA-DR β1-chain. Sets of T cell clones were established from three different HLA-Dw4⁺ responders and compared for their fine specificities. The majority of HLA-DR4 Dw 14 specific T cell clones co-recognized HLA-DR1 Dw1⁺ (33 to 36% of all T cell clones) or HLA-DRwl4 Dw16⁺ (26 to 33%) stimulators, both of which share very similar sequences in the third hypervariable region of the HLA-DR β1-chain with the HLA-DR4 alleles Dw4 and Dw14. These data suggest that sequence and structural similarities in the α-helical portions of the HLA-DR molecule impose a strong bias on the recognition of allotargets. The second haplotype of the responder did not appear to affect the typical fingerprint of T cell recognition except for the deletion of self-reactive TCR specificities. Nonrandom usage of TCR specificities in anti-HLA-DR responses was also found for HLA-DRw11/DRw13⁺ and HLA-DRw11/ DR7⁺ T cell donors who did not share any obvious polymorphic sequence stretches with the allostimulators HLA-DR4 Dw4 or Dw14. T cell clones from an HLA-DRw11/DRw13⁺ responder functionally resembled the TCR specificities derived from the HLA-DR4 Dw4⁺ donors. T cell clones derived from an HLA-DRw11/DR7⁺ individual were characterized by a distinct cross-reactivity pattern preferring HLA-DRw13 Dw19⁺ (50 to 60%) and HLA-DR3⁺ (43 to 57%) stimulator cells. These findings suggest that the responder HLA-DR alleles influence the structural constraints in the recognition of allo-HLA-DR molecules in closely related and in completely disparate responder/stimulator combinations.