Research Article: Roles of the Src Tyrosine Kinases Lck and Fyn in Regulating γδTCR Signal Strength

Date Published: January 26, 2010

Publisher: Public Library of Science

Author(s): Renee M. Laird, Sandra M. Hayes, Jose Alberola-Ila.

Abstract: Lck and Fyn, members of the Src family of tyrosine kinases, are key components of the αβTCR-coupled signaling pathway. While it is generally accepted that both Lck and Fyn positively regulate signal transduction by the αβTCR, recent studies have shown that Lck and Fyn have distinct functions in this signaling pathway, with Lck being a positive regulator and Fyn being a negative regulator of αβTCR signal transduction. To determine whether Lck and Fyn also differentially regulate γδTCR signal transduction, we analyzed γδ T cell development and function in mice with reduced Lck or Fyn expression levels. We found that reducing Lck or Fyn levels altered the strength of the γδTCR signaling response, with low levels of Lck weakening γδTCR signal strength and low levels of Fyn augmenting γδTCR signal strength. These alterations in γδTCR signal strength had profound effects not only on αβ/γδ lineage choice, but also on γδ thymocyte maturation and γδ T cell effector function. These results indicate that the cellular levels of Lck and Fyn play a role in regulating the strength of the γδTCR signaling response at different stages in the life of the γδ T cell.

Partial Text: Signaling by the TCR is required at multiple stages in the life of a T cell. In the thymus, TCR signaling is necessary for lineage commitment and repertoire selection, while in the periphery, TCR signaling is necessary for maintenance of the peripheral T cell pool and for activation and differentiation of mature T cells. Lck and Fyn, two members of the Src family of tyrosine kinases (SFKs), are involved in initiating the TCR-coupled signaling cascade [1], [2]. Following TCR engagement, Lck and/or Fyn phosphorylate the tyrosines within the ITAMs of the CD3 and TCRζ chains. This proximal signaling event leads to the recruitment of other signaling molecules to the TCR signaling complex and to the subsequent activation of signaling pathways that ultimately lead to the nucleus and initiation of gene transcription.

Since SFKs have both positive and negative roles in receptor signaling, it has been postulated that these kinases function more like rheostats than on/off switches [45]. Our data support this idea, as changes in the cellular levels of Lck or Fyn at different stages in the life of a γδ lineage cell affected the strength of the γδTCR signaling response and, in turn, affected αβ/γδ lineage commitment, γδ T cell maturation and γδ T effector cell differentiation.



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