Function Of Il-2-Inducible T Cell Kinase (Itk) In Innate T Cells And Mast Cells
IL-2-inducible T cell kinase (ITK) is expressed in T lymphocytes and mast cells (MC), and functions as a critical signaling mediator downstream of numerous cell surface receptors. ITK regulates both adaptive and innate immunity, via regulation of cell differentiation and activation. Lack of ITK results in spontaneous memory acquisition in [alpha][beta] T cells termed "innate memory phenotype (IMP) T cells". The development and function of IMP T cells, and the role of ITK in their development remains unknown. This dissertation describes an alternative bone marrow transplantation system, which generates murine models with predominant naïve or IMP T cells, allowing comparative investigation of the functions of these cells in vivo; and demonstrates that: 1) IMP T cell development requires hematopoietic expression of major histocompatibility complexes; 2) IMP CD8+ T cells are not the result of T cell homeostatic proliferation (HP), and they can rapidly and potently respond to primary antigenic stimulation; and 3) IMP CD4+ T cells can suppress autoimmune graft-versus-host disease. In addition, this dissertation also investigates the T cell-intrinsic role of ITK in the development of both IMP and HP CD8+ T cells: 1) ITK tunes IL-4/TcR signaling synergy to regulate IMP CD8+ T cell differentiation; and 2) ITK suppresses CD8+ T cell HP and anti-tumor immunity. Loss of ITK in mice also results in hyper-production of immunoglobulin E (IgE), through which MC regulate the development of allergy. Differential functions of ITK and the homologous Bruton's tyrosine kinase (BTK) in MC response to allergen/IgE-mediated stimulation have been illustrated. This dissertation further shows a redundant function for ITK/BTK in MC response to the bacterial endotoxin lipopolysaccharide (LPS), in that lack of ITK and BTK leads to hyper-production of MC-derived TNF-[alpha], which exacerbates LPS-induced septic hypothermia. This work provides insights into the function of ITK in innate T cells, and the value of targeting ITK to enhance antigen-specific primary response by IMP CD8+ T cells, regulatory function of IMP CD4+ T cells, and expansion of anti-tumor HP CD8+ T cells, for therapeutic purposes. However, the MC response to LPS also raises concern on the potential use of ITK/BTK cross-reactive kinase inhibitors.
IL-2-inducible T cell kinase (ITK); Innate T cells; Mast cells
Collins, Ruth N.; Yen, Andrew; Leifer, Cynthia Anne; Linder, Maurine E.
Ph. D., Pharmacology
Doctor of Philosophy
dissertation or thesis