Abstract

Chemokines are important chemical signals that guide lymphocyte movement within the immune system and promote the organization and functions of germinal centers (GCs) in the secondary lymphoid tissues. Previous studies have shown that GC T cells exhibit high expression of chemokine receptor 4, CXCR4, but that these cells are unable to migrate to the ligand for this receptor, the chemokine CXCL12. This “migratory paralysis” to CXCL12 was found to be correlated with the expression of two Regulators of G-protein Signaling, RGS13 and RGS16 in the GC T cells. The objective of my research was to determine whether RGS13 and RGS16 expression were associated with CXCL12-mediated CD4+ T cell migration. Because human GC T cells are rare and vary from one individual to another, I utilized two human neoplastic CD4+ T cell lines (i.e. Hut78 and SupT1) to facilitate and standardize my research. I also confirmed my observations using primary CD4+ T cells. Hut78 cells behaved similarly to GC T cells interms of CXCL12-mediated migration and RGS13 and RGS16 expression, while SupT1 cells appeared similar to CD4+ T cells that resided outside of GCs. The effect of RGS13 and RGS16 expression in the various CD4+ T cells was examined by altering the natural levels of these genes using RNA-mediated silencing and/or gene overexpression analysis after which, I examined the ability of the cells to migrate to CXCL12. RNA-mediated silencing of RGS16-, but not RGS13-, expression in Hut78 T cells resulted in a doubling of the migration rate in response to CXCL12. Over-expression of RGS13 or RGS16 in SupT1 and primary CD4+ T cells resulted in migration that was decreased by fifty percent. Because GC T cells demonstrated decreased migration to CXCL12 signals that may help them leave the GC, I reasoned that these cells may have an increased opportunity over other CD4+ T cells to become infected by the Human Immunodeficiency Virus (HIV) trapped on Follicular Dendritic Cells in the GCs of infected subjects. Examination of GC T cells obtained from HIV-infected subjects indicated that these cells were more frequently infected by HIV than other CD4+ T cells thereby confirming my postulate. My research indicated that RGS13 and RGS16 were associated with CXCL12-mediated CD4+ T cell migration and suggests that these molecules may play an important role in HIV pathogenesis within the GC.

Degree

MS

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

Rights

http://lib.byu.edu/about/copyright/

Date Submitted

2008-08-06

Document Type

Thesis

Handle

http://hdl.lib.byu.edu/1877/etd2588

Keywords

chemokine, regulator of G-protein signaling (RGS), cell migration, germinal center, T cell, HIV

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