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Regulation of Effector/Memory T Cell Activation by Inducible Co-Stimulator (ICOS)

Franko, Jennifer Lynne
http://rave.ohiolink.edu/etdc/view?acc_num=case1228358364

Abstract Details

2009, Doctor of Philosophy, Case Western Reserve University, Pathology.
Inducible Co-stimulator (ICOS) regulates effector/memory T cell activation by enhancing proliferation and cytokine production. However, the mechanisms by which ICOS ligation induces these responses have yet to be defined. We have identified both antigen dependent and antigen independent properties associated with ICOS ligation, each of which functions to promote T cell activation. In the absence of antigen, ICOS functions as an adhesion molecule, promoting effector T cell/APC conjugate formation. Subsequent ICOS-mediated cytoskeletal modifications inhibit cell motility, induce T cell spreading, and stimulate filopodia/microspike elaborations, thereby enhancing antigen recognition by promoting T cell scanning of the APC surface. While ICOS-mediated adhesion occurs independently of its ability to induce intracellular signals, T cell elongation and the anti-migratory phenotype are dependent upon PI-3 K activation, which decreases RhoA activity. Following antigen recognition, ICOS functions as a classical co-stimulatory molecule, augmenting TCR-mediated signal transduction pathways leading to T cell proliferation and cytokine production. In contrast to CD28, in which its proximity to the TCR is not important to enhance TCR-mediated T cell proliferation, ICOS co-stimulation requires both TCR and ICOS signals to be provided on the surface. While this may suggest that ICOS ligation augments functional responses by increasing the number of TCRs engaged, ICOS co-stimulation does not alter the intensity or kinetics of TCR-associated membrane proximal signaling events. Instead ICOS co-stimulation enhances and prolongs second messenger signals emanating from the TCR, as demonstrated by a delayed synergy in the elevated phosphorylation of the downstream effector molecules Akt and Erk 1/2 following co-stimulation.
Alan Levine, Ph.D. (Advisor)
George Dubyak, Ph.D. (Committee Chair)
James Finke, Ph.D. (Committee Member)
Gary Landreth, Ph.D. (Committee Member)
Clive Hamlin, Ph.D. (Committee Member)
160 p.
Immunology
human T cells; signal transduction; cell adhesion; co-stimulation; Rho-GTPases; filopodia; microspikes; cytosolic extensions

Recommended Citations

Citations

  • Franko, J. L. (2009). Regulation of Effector/Memory T Cell Activation by Inducible Co-Stimulator (ICOS) [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1228358364

    APA Style (7th edition)

  • Franko, Jennifer. Regulation of Effector/Memory T Cell Activation by Inducible Co-Stimulator (ICOS). 2009. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1228358364.

    MLA Style (8th edition)

  • Franko, Jennifer. "Regulation of Effector/Memory T Cell Activation by Inducible Co-Stimulator (ICOS)." Doctoral dissertation, Case Western Reserve University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1228358364

    Chicago Manual of Style (17th edition)

case1228358364
583
© 2008, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.