The formation and functions of the 21- and 23-kDa tyrosine-phosphorylated TCRζ subunits

The interaction between the T cell receptor (TCR) and its cognate antigen/major histocompatibility complex (MHC) complex activates a cascade of intracellular protein phosphorylations within the T cell. The signals are initiated by the specific phosphorylation of two tyrosine residues located in a conserved sequence motif termed an ITAM (immune receptor-based tyrosine activation motif). There are 10 ITAMs in the TCR complex, and 6 of these ITAMs are present in the TCRζ homodimer. Following TCR stimulation, the TCRζ subunit forms two tyrosine-phosphorylated intermediates of 21- and 23-kDa, respectively. The dramatic and diverse biological responses of T cells are proposed to be partly regulated by the relative ratios of the 21- vs. 23-kDa phosphorylated forms of TCRζ that are induced following TCR ligation. In this review, we describe a stepwise model of ζ phosphorylation required for the formation of these two phosphorylated derivatives. We describe the kinases and phosphatases controlling these phosphorylation processes. In addition, we present some preliminary findings from ongoing studies that discuss the contributions of each phosphorylated form of ζ on T cell development, TCR signaling, T cell anergy induction, and T cell survival.