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Abstract

The co-receptor CD8 plays an important part in the proper functioning of cytotoxic T lymphocytes. In order to sense stimuli, the T cell surface recep- tor (TCR) engages peptide-specifically with its ligand pMHC, while CD8 makes peptide-unspecific contact to the MHC subunit. In this work, the entirety of interactions between TCR, CD8, and pMHC are elucidated by confronting of a family of mathematical pMHC-TCR-CD8 interaction mod- els with accurately measured dose response data. The interaction model being in best agreement with the data, termed CBM, consists of a TCR- CD8 complex having the striking property that its CD8 subunit exhibits increased affinity to pMHC compared to CD8 alone. A T cell triggering model, founded on multivalent binding, is con- structed that enables affinity-based ligand discrimination. In combination with CBM, the TCR triggering model is capable to correctly predict key aspects of dose response T cell activation data, and introduces a novel mechanism for the contribution of CD8 in ligand discrimination and T cell activation. The high affinity CD8 binding site of the TCR-CD8 complex prevents low affinity (self) ligands to establish pMHC-TCR contacts and thereby reducing the intracellular signal intensity in response to self pep- tides. High affinity (foreign) ligands, on the other hand, can counteract by forming pMHC-TCR contacts with TCR-CD8 complexes. Because CD8 also binds the kinase Lck, this leads to enhanced intracellular signal in- tensity in response to foreign antigen. Thus, CD8 amplifies affinity-based ligand discrimination and the proposed mechanism leads to improved self tolerance as well as sensitivity towards foreign antigen of T cells allocating CD8 a significant contribution to T cell immunity.