T‐cell receptor proximal signaling via the Src‐family kinases, Lck and Fyn, influences T‐cell activation, differentiation, and tolerance

Abstract

T-cell development in the thymus and activation of mature T cells in secondary lymphoid organs requires the ability of cells to respond appropriately to environmental signals at multiple stages of their development. The process of thymocyte selection insures a functional T-cell repertoire, while activation of naive peripheral T cells induces proliferation, gain of effector function, and, ultimately, long-lived T-cell memory. The T-cell immune response is initiated upon engagement of the T-cell receptor (TCR) and coreceptor, CD4 or CD8, by cognate antigen/major histocompatibility complexes presented by antigen-presenting cells. TCR/coreceptor engagement induces the activation of biochemical signaling pathways that, in combination with signals from costimulator molecules and cytokine receptors, direct the outcome of the response. Activation of the src-family kinases p56(lck) (Lck) and p59(fyn) (Fyn) is central to the initiation of TCR signaling pathways. This review focuses on our current understanding of the mechanisms by which these two proteins orchestrate T-cell function.

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

“…In T cells, LCK functions to mediate antigen receptor signaling (32). Although LCK is expressed in B cells, a potential role in BCR signaling has also been proposed (23,24).…”

“…This approach was used in preference to directly immunoprecipitating LCK and examining it for activity (as we did for Lyn) for technical reasons; immunoprecipitation of LCK from CLL cells lysed with mild detergent buffers to lead to coimmunoprecipitation of other SFKs that interfered with assays measuring kinase activity (data not shown), and the use of strong detergent buffers to lyse CLL cells either inhibited our ability to immunoprecipitate LCK or interfered with assays measuring kinase activity. Because anti-pY 416 -Src antibody also cross reacts with pY 394 , the phosphorylation of which depends on LCK activity (32), immunoprecipitated LCK will be in an active conformation. Figure 2F shows that detectable levels of active Lck were present in resting CLL cells, and that incubation of CLL cells with the tyrosine phosphatase inhibitor mpV pic markedly increased these levels.…”

Dok‐1 overexpression promotes development of γδ natural killer T cells

“…Development signals from the pre-TCR and from the TCR are controlled by the coordinated activity of tyrosine kinases such as Syk-family kinases [5], Src-family kinases [6], and Tec-family kinases [7,8] and adaptor molecules such as SLP-76 [9], LAT [10], Grb2 [11], and Gads [12].…”

“…Therefore, signaling molecules that modulate TCR signal strength play a pivotal role in the regulation of T-cell development and homeostasis. Development signals from the pre-TCR and from the TCR are controlled by the coordinated activity of tyrosine kinases such as Syk-family kinases [5], Src-family kinases [6], and Tec-family kinases [7,8] and adaptor molecules such as , LAT [10], Grb2 [11], and Gads [12].Dok are adaptor proteins that contain a pleckstrin homology domain, a phosphotyrosine binding domain, and a COOHterminal region containing multiple tyrosine phosphorylation sites [13,14]. Dok-1 and Dok-2, the two members of Dok family proteins expressed in T cells, are involved in signaling downstream of a variety of receptors in hematopoietic cells (reviewed in [15,16]).…”

“…Therefore, signaling molecules that modulate TCR signal strength play a pivotal role in the regulation of T-cell development and homeostasis. Development signals from the pre-TCR and from the TCR are controlled by the coordinated activity of tyrosine kinases such as Syk-family kinases [5], Src-family kinases [6], and Tec-family kinases [7,8] and adaptor molecules such as , LAT [10], Grb2 [11], and Gads [12].…”