A role for regulatory T cells in gender-biased disease susceptibility to murine lupus.

Systemic lupus erythematosus;Autoimmunity;Regulatory T cells;Sex differences;CD103

Colleen Tucker

University:University of Louisville

Department:Microbiology and Immunology

关键词: Systemic lupus erythematosus;    Autoimmunity;    Regulatory T cells;    Sex differences;    CD103;   

Others  :  https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=2464&context=etd

美国|英语

来源: The Universite of Louisville's Institutional Repository

【 摘 要 】

Females are more susceptible to autoimmune disease than males. In several mouse models of disease, castration of males exacerbates disease while androgen treatment ameliorates disease. These data suggest hormones can have an influence on disease susceptibility and progression. Regulatory T cells (Tregs), particularly the CD4+CD25+ Tregs, have been shown to be important in controlling autoimmune disease. Studies have shown that depleting regulatory T cells can cause severe autoimmune disease, and increasing regulatory T cell population size can protect from disease. We hypothesized that gender differences in regulatory T cell populations would correlate with differences in disease susceptibility. We used a spontaneous mouse model of systemic lupus erythematosus, (NZBxNZW)F1 (BWF1), in which only females develop full-blown kidney disease to investigate gender differences in regulatory T cell percentages and function between females and males and their relationship to disease development. First, we assessed differences in regulatory T cell function and number between young (before disease onset) female mice from four different strains, two autoimmune-prone strains, BWF1 and SJL, and two more autoimmune-resistant strains, CS7BL/6 and BALB/c. We found no differences in in vitro suppressive function by CD4+CD2S+ Tregs from any of the four strains when co-cultured with either syngeneic CD4+CD2Y responders and APCs or CS7BL/6 CD4+CD2Y responders and APCs. We did, however, find lower percentages of CD4+ cells that expressed Foxp3 (CD4+Foxp3+ cells) in the periphery of BWF1 mice when compared to the other three strains of mice. The CD4+CD2S+CDI03+ cells are a potent memory/effector subset of regulatory T cells that are better suppressors than CD4+CD2S+CDI03- Tregs both in vitro and in vivo. As found with the CD4+CD2S+ Tregs, we also found no differences in the suppressive function of CD4+CD2S+CD103+ cells from any of the four strains of mice. However, percentages of CD4+CD2S+CDI03+ cells were, again, decreased in the periphery of BWF1 mice compared to the other three strains. We found that reduced percentages of both CD4+Foxp3+ and CD4+CD2S+CD103+ cells in the periphery of BWF1 mice were not due to defects in either thymic production or homeostatic proliferation of these cells. These data suggest that it may be the decreased Treg:Teffector cell ratio, and not a defect in inherent suppressive function, that render BWF1 mice more susceptible to autoimmune disease. We next examined gender differences in regulatory T cell function and number between young female and male mice of the four strains. We found no differences in the suppressive ability of either