T cell activation enhancement by endogenous pMHC acts for both weak and strong agonists but varies with differentiation state

Abstract

T cells are extremely sensitive in their ability to find minute amounts of antigenic peptide in the midst of many endogenous peptides presented on an antigen-presenting cell. The role of endogenous peptides in the recognition of foreign peptide and hence in T cell activation has remained controversial for CD8+ T cell activation. We showed previously that in a CD8+ T cell hybridoma, nonstimulatory endogenous peptides enhance T cell sensitivity to antigen by increasing the coreceptor function of CD8. However, others were not able to detect such enhancement in naive and activated CD8+ T cells. Here, we show that endogenous peptides substantially enhance the ability of T cells to detect antigen, an effect measurable by up-regulation of activation or maturation markers and by increased effector function. This enhancement is most pronounced in thymocytes, moderate in naive T cells, and mild in effector T cells. The importance of endogenous peptides is inversely proportional to the agonist activity of the stimulatory peptide presented. Unlike for CD4+ T cells, the T cell receptor of CD8+ T cells does not distinguish between endogenous peptides for their ability to enhance antigen recognition.

How a T Cell Receptor-like Antibody Recognizes Major Histocompatibility Complex-bound Peptide

“…Meanwhile, it is thought that CD8/ MHC-I interactions, which occur prior to pMHC recognition by TCR, could influence TCR association with MHC and, consequently, TCR orientation over MHC (22,30). That 25-D1.16 assumes the same orientation over the pMHC ligand as TCR supports the notion that TCR has an intrinsic propensity for MHC (31) and that MHC, not CD8, determines selection of TCRs that bind with canonical orientation.…”

Increased Mobility of Major Histocompatibility Complex I-Peptide Complexes Decreases the Sensitivity of Antigen Recognition

“…These authors proposed that CD8 increases the local density of MHC I-peptide complexes in the synapse and vice versa and that this enhances the sensitivity of antigen recognition. Costimulation by irrelevant peptides was most pronounced on thymocytes, moderate on naive T cells, and mild on effector T cells (48).…”

Phenotypic models of T cell activation

“…14). This is thought to be caused by the recruitment of CD8 to the immunological synapse in a peptide-independent but MHC-dependent manner 56 . Similar results have been found for CD4 (REF.…”

“…These antagonist ligands are typically altered peptide ligands of the agonist that have a shorter dissociation time 51,53,54 . Interestingly, self-pMHC complexeswhich are expected to have shorter dissociation times than antagonists -have been suggested to act synergistically with the agonist, leading to enhanced T cell responses 55,56 . It is reasonable to assume that within the limit of very short dissociation times, the pMHC complex will no longer interact with the TCR and such null pMHC complexes are expected to have no effect on T cell activation.…”