Jonathan D . Ashwell Immune Recognition

Sooner or later, most immunologists must deal with the phenomenon of cellular 'activation'. Lymphocytes normally exist in a resting, or quiescent, state. On receipt of some external stimulus, the cells undergo a cascade of 'activation events' culminating in biological function. For T cells, occupancy of the T cell antigen-specific receptor (TCR) by its ligand (the combination of a peptide antigen and a major histocompatibility complexencoded protein) is the principal physiological stimulus. The TCR consists of two functionally distinct portions: a ligand-binding, structurally variable heterodimer, typically composed of the disulfide-linked 0t and [3 chains, and five invariant chains that comprise the CD3 complex (y, 8 and e) and a ~--~ homodimer or a ~-q heterodimer [1]. Occupancy of the TCR, or its cross-linking by specific antibody, triggers the activity of a phospholipase C, resulting in the hydrolysis of phosphatidylinositol 4,5 hisphosphate to diacylglycerol (activating protein kinase C) and inositol trisphosphate (causing an increase in intracellular Ca 2 +). In addition, one or more protein tyrosine kinases are activated, which phosphorylate, among other substmtes, the TCR itself (on the ~ chain) (Fig.l). Recent data suggest that phospholipase C is coupled to the TCR via a tyrosine kinase, as two independent tyrosine kinase inhibitors prevent activation-induced increases in inositol phosphates and intracellular Ca 2 + [2,3]. The physiological roles of these different signal transduction pathways are not totally clear, but either or both are likely to lead to late phenotypic cellular responses, such as the secretion of intedeukin-2 (IL-2).