CD3 chains associated with calnexin or with TCR molecules are first expressed and used by T cells early during their intrathymic development. Accordingly, CD3 deficiencies strongly influence early T-cell differentiation events, including the up-regulation of the TCR/ CD3 complex itself. Available data from human and murine CD3 deficiencies indicate that CD3 chains play specialized roles in the support of TCR chains and the transduction of signals that emanate from them. Because expression (or aggregation) is a requirement for signaling, the chains that are crucial supporters also strongly affect signaling. CD3ε and ζ, which occur in pairs in the minimal TCR/CD3 complex (see Fig. 1), seem to be important supporters, because inactivating their genes virtually abolishes TCR/CD3 expression. CD3-γ and δ, in contrast, are less crucial for TCR/CD3 expression, particularly by CD4⁺ cells, but they do have dissimilar signaling roles; CD38, but not CD37, is apparently dispensable for the development and TCR expression of the γδ T-cell lineage.

T lymphocytes cannot predict the isotype (αβ, γδ and surrogates thereof) or the specificity (CD1, MHC class I or class II) of the particular TCR with which they are endowed. They do not know whether their TCR has to transduce maturation/activation, anergy or apoptosis signals, or whether it has to aggregate, for instance, with CD4 or CD8 or with CD45RA or RO for antigen recognition. They may carry a range of adaptor CD3 chains capable of supporting and signalling for different TCR ensembles (αβ, γδ, pTαβ, calnexin) in different phenotypic backgrounds (CD4, CD8) and with different functional outcomes (maturation/activation, anergy, apoptosis). Because of the large extracellular domains of CD3γ, δ, and ε, the authors favor the interpretation that these CD3 chains fulfil selective extracellular docking or bumper roles in the macromolecular ensemble that recognizes antigens. Intracellularly, they may be linked to selective downstream signaling pathways. CD3γ, for instance, seems to be dispensable for inducing a proliferative or cytolytic response and TNF-α, but not IL-2 synthesis, in mature αβ T cells. Testing for a broader range of TCR-induced events in human and murine CD3-deficient mature T cells may shed light on the common and selective roles of CD3 chains in the TCR/CD3 complex.