Naive and antigen experienced T cells have different sensitivity to mixed TCR triggering

Delivery of T cell epitopes on Igs operates via the endocytic pathway and grants the peptide access to newly synthesized MHC molecules. When PLP1, a peptide corresponding to proteolipid protein (PLP) amino acids 139-151, was expressed on Ig the resulting Ig-PLP1 was presented to T cells 100 fold better than free PLP1. When PLP-LR, an antagonist of PLP1, was expressed on an Ig, the resulting Ig-PLP-LR was also efficiently presented to T cells and displayed a broad antagonism. Immunization of SJL/J mice with either Ig-PLP1 or Ig-PLP-LR induced a cross-reactive response to both PLP1 and PLP-LR peptides. However, immunization with free peptides generated responses devoid of cross-reactivity. Despite the cross-reactivity, when the chimeras were injected into mice together proliferative responses to both peptides were down-regulated, and IL-2 production was decreased to background levels. Conversely, when T cells from mice immunized with individual chimeras were stimulated with mixtures of PLP1 and PLP-LR there was no down-regulation of proliferative responses or decrease in IL-2 production. These results indicated that Ig-PLP1 and Ig-PLP-LR exert at the level of naive T cells an opposite down-regulation on each other, hindering the response each would independently induce. However, once the T cells have experienced the antigen they support cross-reactivity with PLP1 and PLP-LR peptides. Consequently, naive T cells may be discriminatory and require homogenous TCR triggering for activation and expansion. However once antigen experienced, they tolerate triggering by related peptides and support cross-reactivity.