Date on Master's Thesis/Doctoral Dissertation

12-2005

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Committee Chair

Kosiewicz, Michele Marie

Author's Keywords

T cells; Gender differences; Autoimmune diseases; CD4+CD25+

Subject

Autoimmune diseases--Genetic aspects; Autoimmune diseases--Sex factors; Systemic lupus erythematosus

Abstract

Females have a higher incidence of autoimmune diseases than males for reasons that are currently unknown. CD4+CD25+ regulatory T cells play an important role in the maintenance of immunological homeostasis and self-tolerance by suppressing autoreactive T cells that could potentially cause autoimmune diseases. Given that autoimmune diseases are more prevalent in women compared to men, we hypothesized that sex steroids could influence the incidence and/or progression of autoimmune disease through an effect on CD4+CD25+ regulatory T cell number and/or function. The overall objective of this project was then to determine whether sex steroids mediate sex-based differences in CD4+CD25+ regulatory T cell number, function and phenotype, and through this mechanism influence the differential incidence of systemic lupus erythematosus in females and males. To attain our objectives, we 1) assessed the influence of androgens (dihydrotestosterone) on CD4+CD25+ regulatory T-cell number, phenotype and function; 2) assessed the influence of estrogens (estradiol) on CD4+CD25+ regulatory T cell number and function; 3) assessed CD4+CD25+ T cells and the effects of androgens in an animal model of systemic lupus erythematosus (SLE). We found that androgens increased the numbers of CD4+CD25+, CD4+CD25+CD103+ and CD4+CD25+CTLA4+ cells. Moreover, male CD4+CD25+CD103+ cells expressed more of the regulatory cell-associated transcription factor, Foxp3, than females, which also correlated with an enhancement in in vitro regulatory function, because male CD4+CD25+ and CD4+CD25+CD103+ cells suppressed the proliferation of responder CD4+CD25- cells better than those from females. Conversely, estrogens had a very little effect on regulatory T cell numbers, phenotype and function. Our conclusion was that androgens, but not estrogens, can in fact, have an influence on the numbers, function and phenotype of CD4+CD25+ regulatory T cells. In radiation bone marrow chimera experiments, we determined that androgens increase CD4+CD25+ regulatory cell numbers through an effect on the thymic epithelium, but influence the development of CD4+CD25+ regulatory function through a direct effect on the bone marrow-derived precursor (not mature) cells. In the second part of our project, we assessed CD4+CD25+ T cells and the effects of androgens in a murine model of systemic lupus erythematosus (NZB x NZW) in which only females get disease, and found that female NZB x NZW mice had significantly lower levels of CD4+CD25+ and CD4+CD25+CD103+ T cells compared with male mice. Furthermore, androgen deprivation (castration) led to a reduction in the percentages of CD4+CD25+CD103+ cells in male mice to levels lower than those found in intact male mice, or comparable to levels in intact females. Moreover, male NZB x NZW mice have more potent and greater numbers of CD4+CD25+CD103+ cells. Androgen deprivation in males led to an increase in disease as indicated by the increase in antibodies to dsDNA and a coincident reduction in CD4+CD25+ cell numbers. On the other hand, the administration of androgens to females inhibited disease progression, as reflected in significantly lower levels of dsdNA antibodies compared to placebo-treated females, and this decrease correlated with enhanced CD4+CD25+ cell number and function. Taken together, these data strongly suggest that androgens could influence the incidence and/or severity of disease by affecting the numbers and/or function of regulatory T cells. It also suggests that androgens appear to be associated with an increase in the percentage of CD4+CD25+ cells that express the important trafficking molecule, CD103, which may facilitate the ability of male CD4+CD25+ regulatory cells to reach sites of inflammation. These androgen-mediated changes appear to correlate with prevention of disease, thus androgens may confer, at least in part, resistance to autoimmune disease in males through an enhansive effect on CD4+CD25+ cell numbers and function.

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