T-cell signaling and immunopathologies

Abstract

The understanding of the factors responsible for T-cellsignaling has developed enormously over the past twodecades. Our initial discovery of the CD4- and CD8-p56lckcomplexes and their ability to phosphorylate the T-cellreceptor (TCR) complex led to the discovery of a secondprotein-tyrosine kinase ZAP-70 and an array of adaptorproteins such as LAT and adhesion and degranulation-promoting adaptor protein (ADAP) that are responsible forintegrating TCR signaling events. These pathways are inturn modified by phosphatases such as LYP (PTPN22), E3ligases of the ubiquitin pathway such as Cbl-b and Itch, andco-receptor modules such as signaling lymphocyte activa-tion molecule (SLAM). TCR signals then determine thefunction of T-cells subsets such as regulatory T-cells (Tregs)and follicular helper T-cells (Tfh) in their regulation ofimmune function and autoimmunity. This volume of Semi-nars in Immunopathology provides an up-to-date review ofthe current status of mutations in the TCR signaling cascadeand T-cell subsets that account for immunodeficiencies andautoimmune pathologies.During the past two decades, the field of T-cell signalinghas developed in leaps and bounds. Our initial discovery ofthe CD4- and CD8-p56lck complexes identified theinitiators of the TCR tyrosine phosphorylation cascade inT-cells (i.e., referred to as the “TCR signaling paradigm”)[1–3]. p56lck phosphorylates the antigen-receptor complex[2, 4] in a cascade that leads to the recruitment of anotherkinase termed ZAP-70 to immunoreceptor tyrosine-basedactivation motifs (ITAMs; YxxL x6–8 YxxL) on the CD3and zeta chains [5]. These observations combined withavailability of antiphosphotyrosine-specific antibodies ledto the identification of an array of p56lck, p59fyn, andZAP-70 targets that have served as the mainstay of researchon T-cell activation over the past two decades. Whilep56lck can phosphorylate ITAMs, related src kinase p59fynpreferentially phosphorylates ADAP [6, 7], and ZAP-70targets linker for activation of T-cells (LAT) and 76-kDa srchomology 2 domain-containing leukocyte phosphoprotein(SLP-76) [8, 9]. From this work evolved the identificationof so-called immune cell specific “adaptor proteins” or“molecular scaffolds” that possess discrete moleculardomains or binding sites for the generation of complexes[10–12]. These complexes of proteins integrate TcR signalsfor downstream effecter functions such as cytokine produc-tion [11]. For example, LAT has multiple sites for bindingto phospholipase Cγ1 (PLCγ1), GADS, and growth factorreceptor-bound protein 2 [13, 14], while SLP-76 constitu-tively binds to GADS and has binding sites for Vav1, IL2-inducible T-cell kinase, PLCγ1, 14-3-3, and an SH2domain that binds to ADAP and hematopoietic progenitorkinase 1 [8, 10]. At the same time, key protein-tyrosinephosphatases such as CD45, SHP-1, and LYP have beenuncovered that amplify or dampen the function of thesemolecules by dephosphorylating proteins [15]. Over-arching on this scheme is the ubiquitination pathway, amechanism that controls the expression of signalingproteins [16, 17]. Ubiquitination is controlled by an arrayof E1-E3 ligases that tag proteins for degradation byproteasomes. In addition, co-receptors such as CD28 canamplify the immune response [18, 19]. In this context,SLAM uses a unique recognition mode of tyrosinephosphorylation to induce co-signals [20, 21]. ThesecomponentsinturncanregulatethedevelopmentandfunctionofT-cellsubsets.OfparticularnoteareTRegsandtheircrucialrole in regulating autoimmunity [22]. Given these develop-