Endogenous altered peptide ligand can affect peripheral T cell responses

Using the murine Hb/I-E^k self-antigen model, we have previously identified altered peptide ligands (APLs) which are able to stimulate some but not all TCR-mediated effector functions. To determine the effect of endogenous APL on peripheral T cells, we utilized a TCR transgenic mouse which had reverse our normal antigenic system, with Ser69 peptide being the agonist and Hb(64-76) now being the APL. We show that the constitutive level of endogenous Hb/I-E^k complexes presented by APCs in vivo is too low to affect the response of Ser69 reactive peripheral T cells. However, by increasing the number of Hb/I-E^k complexes expressed by the APCs, both primary T cells and T cell hybridomas are antagonized. We also show that the level of CD4 coreceptor expressed on T cells changes the response pattern to Hb/I-E^k complexes. These results demonstrate that T cells are selected to ignore the constitutive level of endogenous APL/MHC complexes they encounter in the periphery. Peripheral T cell responses can be affected by endogenous complexes under limited but attainable circumstances which change the efficacy of the TCR/ligand interaction.