Structural analysis of human anti-mouse H-2E xenorecognition: T cell receptor bias and impaired CD4 interaction contribute to weak xenoresponses.
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)
Department of Immunology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
P
P
Ramesh
L
L
Barber
J R
JR
Batchelor
R I
RI
Lechler
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006183:H-2 Antigens / Q000737:chemistry / Q000276:immunology*; D015798:HLA-DR1 Antigen / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013329:Structure-Activity Relationship; D014162:Transfection
D000911:Antibodies, Monoclonal; D006183:H-2 Antigens; D015798:HLA-DR1 Antigen; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins