Structural analysis of human anti-mouse H-2E xenorecognition: T cell receptor bias and impaired CD4 interaction contribute to weak xenoresponses

Abstract

T lymphocyte responses to the MHC of an evolutionarily distant species are known to be weak compared with responses against allogeneic MHC products within a species. This fact was used to examine the regions of human MHC class II molecules required for the stimulation of strong primary immune responses against MHC alloantigens. A panel of mouse DAP.3 transfectants expressing the products of wild-type and recombinant DR1/H-2Ek MHC class II genes paired to either DR alpha or H-2E alpha genes was generated, and tested as stimulator cells for purified human T cells. A strong proliferative response to DAP.3 transfectants expressing allogeneic HLA-DR molecules was seen. In contrast, weak or absent responses were recorded against DAP.3 cells expressing H-2E molecules. Substitution of the DR1 beta chain with H-2E beta k led to a dramatic loss of recognition; alpha chain substitution had a less marked effect. Furthermore, replacement of the beta 2 domain of DR1 with H-2E sequence caused 90% inhibition, whereas introduction of the beta 2 domain of DR1 into H-2Ek led to a 10-fold increase in T cell response. These results are most readily explained if the beta 2 domain contributes to the interaction site for the CD4 molecule. Substitution of either half of the beta 1 domain led to a marked loss of response. This was more impressive following substitution of the TCR-contacting alpha-helical region of the domain.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the Interaction of T-Cells with Major Histocompatibility Complex Class II Antigens

“…This raised the possibility that CD4 may stabilize the 'dimer of dimers' and promote the aggregation of TcRs on the surface of the activating T-cell, especially if CD4 itself has a propensity to dimerize [75, 761. It was evident from domain shuffling data [69], CD4 mutagenesis [63,[77][78][79][80][81][82] and antibody binding studies [62, 64, 831 that more than one region within the CD4 molecule is involved in class I1 binding. The data described in this section exploit the species barrier between mouse class I1 molecules and human CD4 [67][68][69]841 to study the role of the a2 domain in T-cell recognition by introducing the a2 domain of murine H-2E into HLA-DR1. It has been shown that the a2 domain appears to contribute to T-cell recognition, and we believe that the most likely explanation for this is that it has a role in CD4 binding, particularly in the light of subsequent mutagenesis data [85].…”