T cell receptor binding to a pMHCII ligand is kinetically distinct from and independent of CD4

Immune recognition of pMHCII ligands by a helper T lymphocyte involves its antigen-specific T cell receptor (TCR) and CD4 coreceptor. We have characterized the binding of both molecules to the same pMHCII. The D10 ap TCR heterodimer binds to conalbumin/I-A(k) with virtually identical kinetics and affinity as the single chain V alphaV beta domain module (scD10) (Kd = 6-8 muM). The CD4 ectodomain does not alter either interaction. Moreover, CD4 alone demonstrates weak pMHCII binding (K-d = 200 muM), with no discernable affinity for the cup TCR heterodimer. Hence, rather than providing a major contribution to binding energy, the critical role for the coreceptor in antigen-specific activation likely results from transient inducible recruitment of the CD4 cytoplasmic tail-associated lck tyrosine kinase to the pMHCII-ligated TCR complex.