Role of the BLTR1 receptor in lymphocyte trafficking

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DESCRIPTION (provided by applicant): With the proposed Mentored Clinical Scientist Development Award, the applicant will build upon her prior experiences studying antigen-specific human CD8+ cells to expand her scientific skills in immunology, cell biology and molecular biology. Dr. Andrew Luster will mentor the principal investigator's scientific development. Dr. Luster is a recognized leader in the field of chemokine biology. He is the Chief of Rheumatology, Allergy and Immunology and has trained numerous postdoctoral fellows. The laboratory of Dr. Luster will provide a rich intellectual environment to foster the candidate's scientific development toward her goal of independent investigation. The proposed study will provide the applicant with an opportunity to utilize in vivo molecular genetic approaches to study basic questions in T lymphocyte trafficking. Leukocyte recruitment and activation are critical for orchestrating host inflammatory responses, and mediators regulating these responses are attractive targets for therapeutic intervention. Leukotriene B4 (LTB4) is a potent lipid chemo-attractant synthesized primarily by myeloid cells. The sponsor identified murine BLTR1 as the high affinity receptor for LTB4 and generated a mouse strain with a targeted deletion of the BLTR1 gene. While BLTR1 has been described as an important functional receptor on myeloid cells that mediates LTB4 function, its expression and function on T cells has not been previously characterized. In preliminary experiments the applicant has demonstrated that BLTR1 is induced upon in vitro T cell activation in effector CD4+ and CD8+ T cells. Additional preliminary data from human subjects and animal models suggests that BLTR1 expressing T lymphocytes may be recruited to sites of inflammation. The applicant will investigate the novel hypothesis that BLTR1 and LTB4 are important for effector T cell trafficking to inflammatory sites, thus serving to link the acquired immune response to the activation of innate immune cells such as neutrophils and macrophages. The applicant specifically proposes to: (1) determine the role of BLTR1 in antigen generated CD4+ and CD8+ trafficking in vivo; (2) determine the role of BLTR1 in Th1 and Th2 cell trafficking; (3) determine the role of BLTR1 in effector CD8+ cell trafficking in a murine model of Listeria monocytogenes infection; (4) determine if BLTR1 expression defines a unique population of human effector T cells.