Structural considerations of T-cell cognizance of antigen

Abstract

Work summarized herein describes two congenic strains of mice, C57BL/10 and B10.BR, which differ at the I-A region of the MHC where C57BL/10 and B10.BR are I-Ab and I-Ak respectively. Using various antigens to stimulate, in vitro, primed T lymphocytes, studies on the responsiveness of these two strains to immunization with TMVP and with its tryptic peptide number 8 representing residues 93-112 of the protein are described. These studies revealed that in the C57BL/10 strain TMVP and peptide 8 exhibit cross reactivity on the T-cell level, whereas in the B10.BR strain these two antigens do not exhibit such cross reactivity. Further studies revealed that the cross reactivity is mapped to the I-A region of the MHC with cross reactivity between TMVP and peptide 8 exhibited in mice with I-Ab (referred to as cross reactive-CR) but not with I-Ak (referred to as non cross reactive-NCR). Cell depletion and reconstitution experiments revealed that cross reactivity (or the lack thereof) could be attributed to antigen presenting cells (APC). A profound difference between the strains was also expressed on the level at which their immune T-cells reacted in vitro to stimulation by various derivatives of peptide 8. The studies suggest that the strains differ in their responsiveness to the various orientations in which the T-cell epitope(s) are presented. Assuming that TMVP, but not peptide 8, is altered during processing by APC and assuming that antigen processing by APC of CR and NCR is similar, the difference which the strains exhibit in recognizing different orientations of the epitope may account for the difference in the cross reactivity between TMVP and peptide 8 exhibited by these strains. Further investigations revealed that the strains also differ in their response to pre-immunization with TMVP prior to immunization with peptide 8. Whereas preimmunization of the C57BL/10 (CR) mice with TMVP did not affect subsequent response to immunization with peptide 8, preimmunization of B10.BR (NCR) mice with TMVP suppressed the response to subsequent immunization with peptide 8. It is suggested that the presentation of the T-cell epitope(s) in the correct orientation by the appropriate Ia is crucial for the activation of T helper cells but that such presentation does not play a decisive role in the activation of T suppressor cells.