The Src Family Kinase Fyn Mediates Signals Induced by TCR Antagonists

Abstract

FcR nonbinding anti-CD3ε mAbs elicit partial TCR signaling that leads to T cell unresponsiveness and tolerance in vivo. In this study, the membrane-proximal events that promote T cell inactivation by FcR nonbinding anti-CD3 mAbs were examined. In the context of FcR nonbinding anti-CD3, TCR complexes did not aggregate and failed to translocate into glycolipid-enriched membrane microdomains. Furthermore, FcR nonbinding anti-CD3 mAbs induced tyrosine phosphorylation of the Fyn substrate Cbl, but not the ZAP-70 substrate linker for activation of T cells. Overexpression of Fyn, but not Lck, restored the mitogenicity of FcR nonbinding anti-CD3 in primary T cells. Taken together, these results suggest that Fyn mediates the partial signaling induced by TCR antagonists.

Lck Is Required for Activation-Induced T Cell Death after TCR Ligation with Partial Agonists

“…Anti-CD3 fos also activates Fyn and induces phosphorylation of SLAP-130, consistent with published data that TCR partial agonists or TCR antagonists induce activation of Fyn (19,25). However, Fyn activation does not seem to play an essential role in AICD under the conditions tested, as T cells with or without Fyn had a comparable susceptibility to apoptosis induced by anti-CD3 fos (Fig.…”

“…For this experiment, we used Agprimed, noncycling T cells, because there was a high level of basal activity for Fyn and Lck in cycling T cells. Anti-CD3 fos induced significant phosphorylation of Fyn as compared to unstimulated controls, consistent with the findings that TCR partial agonists preferentially induce phosphorylation of Fyn (19,25). In fact, the activity of Fyn was higher after stimulation with anti-CD3 fos than with anti-CD3-CD4 fos-jun (Fig.…”

“…4). In contrast, Fyn activation has been shown to be important in the induction of T cell anergy (19,49). Thus, Fyn and Lck activation might be differentially involved in determining T cell anergy vs apoptosis, respectively.…”

“…This partial agonist signaling pattern was characterized by incomplete phosphorylation of TCR and CD3, activation of Fyn, recruitment of -associated protein of 70 kDa (ZAP-70) without phosphorylation and activation of this kinase, attenuated intracellular calcium mobilization, and transient activation of mitogen-activated protein kinases (MAPKs). Partial TCR signaling induces anergy in noncycling T cells (16,18,19) and activation-induced cell death (AICD) through apoptosis in Agactivated, cycling T cells (3,5,20). This AICD requires a TCR signal and expression of one or more death receptor ligands.…”

Casein Kinase 2 (CK2)-Mediated Reduction of the Activities of Src Family Tyrosine Kinases in Vitro

“…The biological functions of Fyn are diversed, and are related to its association with a variety of intracellular signaling molecules and to its phosphorylation of a wide variety of intracellular signaling molecules, such as a-synuclein 6) and a 120 kDa protein of the casitas B-lineage lymphoma (Cbl) protooncogene. 7) It has been reported that (i) CK2 can phosphorylate insulin receptor tyrosine (Tyr)-kinase, 8) and insulin growth factor-II (IGF-II) receptor Tyr-kinase 9) in vitro and in vivo; (ii) the asubunit of CK2 is a target for Abelson murine leukemia (Abl) Tyr-kinase and its complex with cAbl inhibits CK2 activity at the cellular level; 10) and (iii) the a-catalytic activity of CK2 is stimulated through its phosphorylation by either Lyn or c-Fgr in vitro. 11) However, the physiological correlation between these TKs and CK2, and the physiological significance on the CK2-mediated regulation of these TK activities remain to be elucidated.…”