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Regulation of the TCR signaling pathway

Rivera Reyes, Brenda Mariola
http://rave.ohiolink.edu/etdc/view?acc_num=case1132588714

Abstract Details

2006, Doctor of Philosophy, Case Western Reserve University, Pathology.
Activation of T cells through their T cell receptor (TCR) mediates the specificity of an immune response to antigens. The TCR signaling cascade involves the activation of protein tyrosine kinases with the resultant phosphorylation of cellular proteins, ultimately leading to new gene transcription, cytokine production and proliferation of T cells. Complex regulation of the TCR signaling cascade is not surprising since inappropriate cell activation could potentially lead to autoimmune diseases, inflammatory disorders and lymphoid malignancies. In an effort to understand the regulation of the TCR signaling cascade we studied the role of (1) TCR-zeta phosphorylation, (2) CD45 protein tyrosine phosphatase activity and the (3) balance between intracellular glutathione (GSH) and TCR-induced reactive oxygen species (ROS) in the tuning of the response of a T cell to activation. (1) TCR induced IL-2 production is dependent on the phosphorylation status of the æ chain of the TCR/CD3 complex induced by the actions of Src kinases upon TCR activation. In addition, TCR-zeta is constitutively phosphorylated in resting cells contributing to an inhibitory signaling environment. We demonstrate that phosphorylation of TCR-zeta is not entirely mediated by Src family kinases and propose the Tec family kinase, Itk, as a plausible candidate that mediates TCR-zeta phosphorylation in combination with Src kinases. (2) Varying the strength of TCR engagement by stimulation of T cells under different degrees of crosslinking lead to differences in the kinetics and duration of the TCR signaling cascade. We demonstrate that by varying the conditions of TCR engagement the activity of CD45 is affected, leading to Lck inhibition or activation, resulting in different TCR activation patterns. (3) TCR-induced production of H2O2 has been proposed to prolong the TCR signaling cascade since H2O2 reversibly inactivates PTPs. We extended this concept by proposing that elevated intracellular GSH should rapidly detoxify the TCR-induced H2O2 yielding a hyporesponsive T cell. The understanding of these different regulatory mechanisms could be exploited for the design of immune specific therapeutic approaches.
Alan Levine (Advisor)
160 p.
TCR signaling pathway; Protien tyrosine kinases and phosphatases

Recommended Citations

Citations

  • Rivera Reyes, B. M. (2006). Regulation of the TCR signaling pathway [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1132588714

    APA Style (7th edition)

  • Rivera Reyes, Brenda. Regulation of the TCR signaling pathway. 2006. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1132588714.

    MLA Style (8th edition)

  • Rivera Reyes, Brenda. "Regulation of the TCR signaling pathway." Doctoral dissertation, Case Western Reserve University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1132588714

    Chicago Manual of Style (17th edition)

case1132588714
1,180
© 2005, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.