Homing of Th1 cells to sites of Th1 inflammation relies on the interaction of chemokine receptors on Th1 cells with the chemokines secreted at Th1 inflammatory sites. We present preliminary data that STAT1 is the master regulator of Th1 cell trafficking as STAT1-deficiency, but not T-bet deficiency, dramatically impairs the recruitment of adoptively transferred wild-type antigen-specific Th1 cells to inflammatory sites. STAT1 controls Th1 cell trafficking by regulating tissue expression of a subset of chemokines. Finally, antigen-specific Th1 cells that traffic to inflammatory sites preferentially express a select group of chemokine receptors. It is not clear, at this point, which one of these chemokine receptors are critical for trafficking of antigen-specific Th1 cells or what aspect of Th1 inflammation drives the expression of these chemokine receptors on Th1 cells. We hypothesize that a distinct subset of chemokine receptors expressed on antigen-specific Th1 cells is critical for effective trafficking of antigen-specific Th1 cells and that the interferon gamma pathway plays a regulatory role in the expression of these chemokine receptors. We propose to: 1) Determine the cellular source of STAT1, and relevant chemokines, that is critical for recruitment of antigen-specific Th1 cells, using immunohistochemistry staining and bone marrow transplantation experiments. 2) Determine the subset of chemokine receptors that is critical for effective trafficking of antigen-specific Th1 cells in vivo, using adoptive transfer of wild type and chemokine receptor deficient antigen-specific Th1 cells. 3) Determine whether interferon gamma, and/or the transcription factors down stream of interferon gamma signaling, regulate the expression of chemokine receptors on antigen-specific Th1 cells, using in vitro generated antigen-specific Th1 cells deficient in the interferon gamma receptor, STAT1 or T-bet, and quantitative PCR and flow cytometry. With this Mentored Clinical Scientist Development Award, I will build upon my previous training and research experiences, learn a variety of laboratory techniques in immunology, cell and molecular biology and study mechanisms that control Th1 cell trafficking. I will benefit from the mentorship of Dr. Andrew D. Luster, an expert in fileds of chemokines and effector T cell trafficking. My ultimate goal is to focus my research career as an independent investigator on mechanisms of T cell recruitment. As effector T cells orchestrate a wide range of disorders, a better understanding of the pathways that lead to T cell trafficking has far reaching potential benefits for the treatment and prevention of infectious, autoimmune and atopic diseases.
| Mikhak, Zamaneh; Strassner, James P; Luster, Andrew D (2013) Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4. J Exp Med 210:1855-69 |
| Mikhak, Zamaneh; Fukui, Mieko; Farsidjani, Alireza et al. (2009) Contribution of CCR4 and CCR8 to antigen-specific T(H)2 cell trafficking in allergic pulmonary inflammation. J Allergy Clin Immunol 123:67-73.e3 |
| Mikhak, Zamaneh; Farsidjani, Alireza; Luster, Andrew D (2009) Endotoxin augmented antigen-induced Th1 cell trafficking amplifies airway neutrophilic inflammation. J Immunol 182:7946-56 |
