The CD3 γϵ/δϵ signaling module provides normal T cell functions in the absence of the TCR ζ immunoreceptor tyrosine‐based activation motifs

T cell receptor (TCR) signal transduction is mediated by the immunoreceptor tyrosine‐based activation motifs (ITAM). The ten ITAM in the TCR complex are distributed in two distinct signaling modules termed TCR ζζ and CD3 γϵ/δϵ. To delineate the specific role of the ζ ITAM in T cell development and TCR signal transmission, we compared the properties of T cells from different TCR ζ‐transgenic lines wherein tyrosine‐to‐phenylalanine substitutions had been introduced in the ζ subunit. These lines lack selected phosphorylated forms of TCR ζ including just p23, both p21 and p23, or all phospho‐ζ derivatives. We report herein that the efficiency of positive selection in HY TCR‐transgenic female mice was directly related to the number of ζ ITAM in the TCR. In contrast, TCR‐mediated signal transmission and T cell proliferative responses following agonist peptide stimulation were similar and independent of the ζ ITAM. Only the duration of MAPK activation was affected by multiple ζ ITAM substitutions. These results strongly suggest that the ITAM in the CD3 γϵ/δϵ module can provide normal TCR signal transmission, with ζ ITAM providing a secondary function facilitating MAPK activation and positive selection.