Lymphocyte signal transduction

Functional immune responses evolve through an exquisitely controlled process integrating signals from activating and inhibitory receptors on the immune cell surface. These complex interactions, which regulate both the quality and magnitude of the ultimate response, depend crucially on two short, loosely conserved motifs found in the intracellular domain of various signaling proteins. These motifs, termed “ITAMs” and “ITIMs” for immunoreceptor tyrosine-based activation (or inhibititory) motifs, provide the basis for two opposed signaling modules that duel for control of cellular activation within the immune system. Well over a decade ago it was observed that the subunits associated with the B cell and T cell antigen receptors, and the FcεRI receptor shared a sequence motif now known as an ITAM (1, 2), a sequence postulated to link antigenic receptors to their intracellular signaling cascades (1). Since then, numerous studies have demonstrated the importance of these receptor subunits and their ITAMs in generating signals downstream of their associated receptors, providing a framework for understanding how ITAMs regulate immune cell activation. Following the identification of the ITAM, it was observed that the FcγRIIB receptor could inhibit signals through the B cell receptor (BCR) (3), an activity that depended on the presence of an ITIM within the FcγRIIB cytoplasmic tail. Recruitment of specific phosphatases to the tyrosine-phosphorylated ITIM results in the complete inhibition or downmodulation of immune cell effector functions (reviewed in ref. 4). Over the past several years, transmembrane receptors containing ITIMs have been identified on virtually all cells in the immune system and also on some nonhematopoietic cells (reviewed in ref. 4). Interestingly, most of these ITIM-containing transmembrane receptors have homologous activating receptors that associate with ITAM-containing subunits. In this Perspective, we review the molecular interactions of ITAMand ITIM-bearing proteins and consider their importance in regulating the outcome of immune cell stimulation by antigens. ITAMs The activation of many immune cell types occurs through multisubunit cell-surface receptors in which antigen-recognizing or ligand-binding subunits are noncovalently associated with one or more transmembrane adapter molecules. These transmembrane adapter molecules contain a short extracellular region, a transmembrane segment, and a cytoplasmic tail of varying length. Adapters associated with the T cell receptor (TCR), BCR, several activating natural killer (NK) cell receptors, some Fc receptors, and other receptors on hematopoietic cells help transduce signals to these various cell types. Common structural features of these adapter molecules are a conserved aspartic residue within the transmembrane region, which is important for association with receptor-binding subunits, and one or more copies of the ITAM, whose loose consensus sequence is YXXL/I(X6-8)YXXL/I (where X denotes any amino acid) (1, 2). Numerous reports have highlighted the importance of the ITAM in the generation of intracellular biochemical signaling cascades following receptor engagement (reviewed in refs. 5, 6). Depending on the maturation state of the cell or the specific cell type, these signaling cascades can culminate in such diverse biological readouts as developmental maturation, cell death, cell survival, or effector functions including cytokine production and cellular cytotoxicity. The family of ITAM-containing proteins includes the TCR-associated CD3γ, CD3δ, CD3ε, and ζ chains; the BCR-associated Igα and Igβ chains; the FcεRIβ chain; the FcεRI-, the FcγRI-, and the FcγRIII-associated γ chain; DAP12; and several virally encoded transmembrane molecules. In general, the most proximal and requisite event upon receptor engagement is the activation of Src family protein tyrosine kinases (PTKs; see ref. 7 for review). Activation of Src family PTKs leads to the phosphorylation of both tyrosines within the ITAM, which, in turn, leads to the recruitment and activation of the tandem SH2 domain–containing Syk and ZAP-70 tyrosine kinases. The activation of Syk and/or ZAP-70 following binding to the dually phosphorylated ITAM leads to the recruitment and phosITAMs versus ITIMs: striking a balance during cell regulation