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P Cell Activation and Csk Regulation
P Cell activation results from engagement of the T cell receptor (TCR) by antigen peptides and major histocompatibility complex (MHC) molecules displayed by antigen-presenting cells (APCs) (Weiss and Littman, 1994). TCR signaling is instigated by protein tyrosine phosphorylation, which is initiated by Src family enzymes, a group of intracellular protein tyrosine kinases (PTKs) associated with the plasma membrane inner leaflet. The Src kinases in T cells, Lck and Fyn, mediate this effect largely by phosphorylating immunoreceptor tyrosine-based activation motifs (ITAMs) in TCR-associated CD3 and chains. ITAM tyrosine phosphorylation enables recruitment of another PTK, ZAP-70, which phosphorylates other proteins leading to effector functions. The enzymatic activity of Src kinases is regulated by tyrosine phosphorylation (Veillette et al., 2002). Phosphorylation of a tyrosine (Y) in the kinase domain (Y394 in Lck; Y417 in Fyn) leads to activation. This is mediated by autophosphorylation, and reversed by protein tyrosine phosphatases (PTPs) such as PTPN22 and SHP-1. Defects in these phosphatases, in particular PTPN22, are linked to autoimmune diseases in humans (Rhee and Veillette, 2012; Stanford and Bottini, 2014). In contrast, phosphorylation of a carboxyl-terminal tyrosine (Y505 in Lck; Y528 in Fyn) inactivates Src kinases. This is mediated by another PTK, Csk, and is reversed by the transmembrane PTP CD45. Whereas Src kinases are membrane-bound, Csk is cytoplasmic. Thus, Csk needs to bind membrane-associated molecules to be near Src kinases. A strong candidate for recruiting Csk to the plasma membrane is the transmembrane adaptor PAG, also known as Cbp (Brdicka et al., 2000; Hrdinka and Horejsi, 2014; Kawabuchi et al., 2000; Simeoni et al., 2008). Membrane-bound PAG is also targeted to lipid rafts, where large pools of Src kinases reside. PAG is prominently tyrosine phosphorylated in unstimulated T cells (Brdicka et al., 2000; Davidson et al., 2003). This phosphorylation enables binding to Csk, by way of tyrosine 314 (Y314) of PAG and the Src homology 2 (SH2) domain of Csk. Upon TCR stimulation, PAG is dephosphorylated and dissociates from Csk (Brdicka et al., 2000; Davidson et al., 2003; Torgersen et al., 2001). This event is presumed to alleviate the suppressive effect of Csk on Src kinases. In support of the inhibitory role of Csk in TCR signaling, pharmacological inhibition of Csk in adult T cells augmented T cell activation (Manz et al., 2015). Conversely, Csk overexpression in a T cell line suppressed T cell activation (Chow et al., 1993; Manz et al., 2015). Furthermore, Csk-deficient (knock-out; KO) mice exhibited severe T cell developmental abnormalities (Schmedt et al., 1998; Tan et al., 2014).
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Although it had been presumed that PAG mediates membrane recruitment of Csk in T cells, two groups reported that PAG KO mice had no overt T cell phenotype (Dobenecker et al., 2005; Xu et al., 2005; Yang and Seed, 2003). This observation raised the possibility that PAG is not responsible for membrane recruitment of Csk, or, alternatively, that other Csk-binding molecules provide this function in the absence of PAG. To resolve these matters, we further evaluated T cell functions of PAG-deficient mice. As reported (Dobenecker et al., 2005; Xu et al., 2005; Yang and Seed, 2003), PAG KO mice displayed no obvious alterations in T cell development, and had unaltered T cell activation responses when freshly isolated (“naive”) T cells were analyzed. In contrast, these mice displayed increased activation responses in vitro and in vivo when previously activated (“effector”) T cells were assessed. In the absence of PAG, Csk became more extensively associated with alternative Csk-interacting proteins, namely PTPN22 and Dok adaptors, which cooperated with PAG to suppress activation of previously activated T cells. Lastly, unlike mice lacking PAG, PTPN22 or Dok adaptors, mice genetically deficient for Cbl ubiquitin ligases had augmented activation responses in freshly isolated T cells, suggesting that a distinct set of inhibitory effectors, including the Cbl proteins, is controlling TCR signaling in naive T cells.
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