A redundant role of the CD3 gamma-immunoreceptor tyrosine-based activation motif in mature T cell function

At least four different CD3 polypeptide chains are contained within the mature TCR complex, each encompassing one (CD3 gamma, CD3 delta, and CD3 epsilon) or three (CD3 zeta) immunoreceptof tyrosine-based activation motifs (ITAMs) within their cytoplasmic domains. Why so many ITAMs are required is unresolved: it has been speculated that the different ITAMs function in signal specification, but they may also serve in signal amplification. Because the CD3 xi chains do not contribute unique signaling functions to the TCR, and because the ITAMs of the CD3-gamma delta epsilon module alone can endow the TCR with normal signaling capacity, it thus becomes important to examine how the CD3 gamma-, delta-, and epsilon -ITAMS regulate TCR signaling. We here report on the role of the CD3 gamma chain and the CD3 gamma -ITAM in peripheral T cell activation and differentiation to effector function. All T cell responses were reduced or abrogated in T cells derived from CD3 gamma null-mutant mice, probably because of decreased expression levels of the mature TCR complex lacking CD3 gamma. Consistent with this explanation, T cell responses proceed undisturbed in the absence of a functional CD3 gamma -ITAM. Loss of integrity of the CD3 gamma -ITAM only slightly impaired the regulation of expression of activation markers, suggesting a quantitative contribution of the CD3 gamma -ITAM in this process. Nevertheless, the induction of an in vivo T cell response in influenza A virus-infected CD3 gamma -ITAM-deficient mice proceeds normally. Therefore, if ITAMs can function in signal specification, it is likely that either the CD3 delta and/or the CD3 epsilon chains endow the TCR with qualitatively unique signaling functions. The Journal of Immunology, 2001, 166: 2576-2588.