CD8α/α homodimers fail to function as co‐receptor for a CD8‐dependent TCR

Abstract

In this study, we have started to dissect the molecular basis of CD8 dependence of a high and low avidity CTL clone specific for the same peptide epitope. Using anti-CD8a and anti-CD8b antibodies, we found that cytotoxicity and IFN-c production by high but not by low avidity CTL was strongly CD8 dependent. We isolated the TCR genes of both types of CTL clones and used retroviral gene transfer to analyse the function of these TCR in primary T cells of wild-type and CD8b-deficient mice. Both TCR triggered antigen-specific killing in wild-type T cells, and blocking experiments showed that CD8 dependence/independence co-transferred with the TCR into primary T cells, indicating that it was dictated by the TCR itself. Gene transfer experiments into CD8b-deficient T cells revealed that only the TCR derived from the CD8-independent CTL clone elicited antigen-specific cytotoxicity, while the CD8-dependent TCR was non-functional in the absence of the CD8b-chain. These data indicate a striking difference between CD8a/b heterodimers and CD8a/a homodimers as only the former were able to provide coreceptor function for the CD8-dependent TCR.

High affinity soluble ILT2 receptor: a potent inhibitor of CD8+ T cell activation

“…2C). While physiologically CD8αα is non-identical to the natural CD8αβ heterodimer (McNicol et al, 2007), its binding to MHC I mimics one of the two proposed modes of the CD8αβ binding (Chang et al, 2006) and is capable of antagonizing the latter (Sewell et al, 1999). The peptidespecific binding of TCR is unaffected by the bound CD8αα .…”

TCR-MHC docking orientation: natural selection, or thymic selection?

“…Deletion of the CD8b tail eliminates all phosphorylation of CD3f, and Zap70 [98]. It has recently been shown that the aa homodimer cannot substitute for CD8ab heterodimer [99]. Thus, both chains of the heterodimer are important for location and proper function.…”

Duality of the murine CD8 compartment

“…(iv) TCR sequences have been shown to convey CD8 dependence (2,14,(17)(18)(19)(20). (v) The TCR of a CD8-independent CTL engaged its ligands in a noncanonical docking orientation (23).…”

“…However, other studies claim that CD8 dependence is related to TCR sequences and that CD8-independent T cells can express lowaffinity TCR (2,(17)(18)(19)(20). This latter view is supported by the observations that CD8 independence or dependence can be conveyed by TCR gene transfer (18,20) and that the TCR repertoires of CD8-independent, virus-specific CTL from CD8β-or CD8α-KO mice are different from TCR repertoires of such CTL from normal mice (2,14,17). CD8 + (and CD4 + ) T cells are generated by a multistep process in the thymus.…”