Hormonal Regulation of CD4⁺T-Cell Responses in Coxsackievirus B3-Induced Myocarditis in Mice

Abstract

Coxsackievirus B3 infection causes significant cardiac inflammation in male, but not female, B1.Tg.Eα mice. This gender difference in disease susceptibility correlates with selective induction of CD4+ Th1 (gamma interferon-positive) cell responses in animals with testosterone, whereas estradiol promotes preferential CD4+ Th2 (interleukin-4 positive [IL-4+]) cell responses. Differences in immune deviation of CD4+ T cells cannot be explained by variation in B7-1 or B7-2 expression. Infection significantly upregulated both molecules, but no differences were detected between estradiol- and testosterone-treated groups. Significantly increased numbers of activated (CD69+) T cells expressing the γδ T-cell receptor were found in male and testosterone-treated male and female mice. In vivo depletion of γδ+ cells by using monoclonal antibodies inhibited myocarditis and resulted in a shift from a Th1 to Th2 response phenotype. Taken together, our results indicate that testosterone promotes a CD4+ Th1 cell response and myocarditis by promoting increased γδ+ cell activation.

Testosterone-mediated immune functions and male life histories

“…Calzolari (1889) first reported a connection between reproduction and immunology when he observed that male rabbits castrated before sexual maturity had larger thymuses than control animals. Reproductive hormones, in particular androgens with an anabolic effect, can alter immunological responses by altering antigen presentation and cellular apoptosis (Huber et al, 1999). In turn, cytokines can directly affect the hypothalamic-pituitarytesticular axis: IL-1b can suppress rat pituitary luteinizing hormone release (Bonavera et al, 1993), and both IL-1b and TNFa can decrease steroidogenic acute regulatory protein (StAR) gene expression, preventing cholesterol translocation to the mitochondrial membrane of Leydig cells, the primary source of testosterone synthesis in males (Lister and van der Kraak, 2002;Ogilvie et al, 1999).…”

“…The binding of testosterone to androgen receptors on T cells can influence the types and quantity of cytokines they synthesize and release. Some evidence suggests that androgens favor the development of a CD4 þ type-1 phenotype of peripheral lymphocytes and cytokines Giltay et al, 2000;Huber et al, 1999), which may increase susceptibility to certain infections that are cleared via the Th-2 cytokines. Alternative evidence suggests that androgens can diminish proinflammatory cytokine production (specifically IL-1b, TNFa, and IFNg) by macrophages Burger and Dayer, 2002;Grossman et al, 1995;Lin et al, 1996;Smithson et al, 1998;Straub and Cutolo, 2001).…”

“…Reduce B-cell lymphopoiesis and affect antibody production Olsen and Kovacs (1996) 7. Preferentially alter the development of a CD4 þ type-1 phenotype of peripheral lymphocytes and cytokines Huber et al (1999); Giltay et al (2000) 8. Inhibit the expression of nitric oxide synthase in murine macrophages Friedl et al (2000) 9.…”

Influence of Testosterone on Inflammatory Response in Testicular Cells and Expression of Transcription Factor Foxp3 in T Cells

“…12 In support, several studies showed that androgen treatment in vitro inhibits inflammatory responses by promoting anti-inflammatory signaling pathways leading to secretion of IL-10 and TGF-b, while the release of pro-inflammatory mediators such as IL-1b, IL-6, or TNF-a was inhibited. 5,[13][14][15][16][17][18] In the testis, androgen levels are substantially higher than in serum, a fact that has been connected with the so-called immune privilege characteristic of this organ. [19][20][21][22] In the testis, immune privilege has been demonstrated by the ability to tolerate alloand xenoantigens experimentally transplanted in this organ.…”

“…American Journal of Reproductive Immunology 74 (2015)[12][13][14][15][16][17][18][19][20][21][22][23][24][25] …”