CD8 controls T cell cross-reactivity.

Estimates of human αß TCR diversity suggest that there are <10(8) different Ag receptors in the naive T cell pool, a number that is dwarfed by the potential number of different antigenic peptide-MHC (pMHC) molecules that could be encountered. Consequently, an extremely high degree of cross-reactivity is essential for effective T cell immunity. Ag recognition by T cells is unique in that it involves a coreceptor that binds at a site distinct from the TCR to facilitate productive engagement of the pMHC. In this study, we show that the CD8 coreceptor controls T cell cross-reactivity for pMHCI Ags, thereby ensuring that the peripheral T cell repertoire is optimally poised to negotiate the competing demands of responsiveness in the face of danger and quiescence in the presence of self.

Modification of MHC anchor residues generates heteroclitic peptides that alter TCR binding and T cell recognition.

Improving T cell Ags by altering MHC anchor residues is a common strategy used to enhance peptide vaccines, but there has been little assessment of how such modifications affect TCR binding and T cell recognition. In this study, we use surface plasmon resonance and peptide-MHC tetramer binding at the cell surface to demonstrate that changes in primary peptide anchor residues can substantially and unpredictably alter TCR binding. We also demonstrate that the ability of TCRs to differentiate between natural and anchor-modified heteroclitic peptides distinguishes T cells that exhibit a strong preference for either type of Ag. Furthermore, we show that anchor-modified heteroclitic peptides prime T cells with different TCRs compared with those primed with natural Ag. Thus, vaccination with heteroclitic peptides may elicit T cells that exhibit suboptimal recognition of the intended natural Ag and, consequently, impaired functional attributes in vivo. Heteroclitic peptide-based immune interventions therefore require careful evaluation to ensure efficacy in the clinic.

MHC class I molecules with Superenhanced CD8 binding properties bypass the requirement for cognate TCR recognition and nonspecifically activate CTLs.

CD8(+) CTLs are essential for effective immune defense against intracellular microbes and neoplasia. CTLs recognize short peptide fragments presented in association with MHC class I (MHCI) molecules on the surface of infected or dysregulated cells. Ag recognition involves the binding of both TCR and CD8 coreceptor to a single ligand (peptide MHCI [pMHCI]). The TCR/pMHCI interaction confers Ag specificity, whereas the pMHCI/CD8 interaction mediates enhanced sensitivity to Ag. Striking biophysical differences exist between the TCR/pMHCI and pMHCI/CD8 interactions; indeed, the pMHCI/CD8 interaction can be >100-fold weaker than the cognate TCR/pMHCI interaction. In this study, we show that increasing the strength of the pMHCI/CD8 interaction by approximately 15-fold results in nonspecific, cognate Ag-independent pMHCI tetramer binding at the cell surface. Furthermore, pMHCI molecules with superenhanced affinity for CD8 activate CTLs in the absence of a specific TCR/pMHCI interaction to elicit a full range of effector functions, including cytokine/chemokine release, degranulation and proliferation. Thus, the low solution binding affinity of the pMHCI/CD8 interaction is essential for the maintenance of CTL Ag specificity.