Androgen Receptors in Thymic Epithelium Modulate Thymus Size and Thymocyte Development (original) (raw)
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Androgen Receptors in Thymic Epithelium Modulate Thymus Size and Thymocyte Development 1
Endocrinology, 2001
Castration of normal male rodents results in significant enlargement of the thymus, and androgen replacement reverses these changes. Androgen-resistant testicular feminization (Tfm) mice also show significant thymus enlargement, which suggests that these changes are mediated by the androgen receptor (AR). The cellular targets of androgen action in the thymus are not known, but may include the lymphoid cells (thymocytes) as well as nonlymphoid epithelial cells, both of which have been believed to express AR. In the present study immunohistochemical analysis and hormone binding assays were used to demonstrate the presence of AR in thymic epithelial cells. The physiological significance of this epithelial cell AR expression was defined by further studies performed in vivo using
Increased Thymic Size and Thymocyte Interleukin 2 Production in Androgen-Resistant Mice
Scandinavian Journal of Immunology, 1989
The functional significance of androgen receptors in thymocytes is unknown. To investigate whether such receptors mighl mediate androgen-induced eftecls on thymocyle proHreration or differentiation we examined mice bearing a known defect in the gene coding for the androgen receptor. This mutalion. termed testicular feminization (Tfm/Y). renders these mice resistant to the action of androgenic hormones. Testicular feminization mice were found to have large Ihymuses that were an average of 2.8 times as heavy as those of their unaffected male litler mates, and contained up to 36 times as many thymocytes. Similar findings were observed when Tfm mice were compared with C57BI/6 control mice. Thymocytes from androgen-resistant mice produced several limes more inlerleukin 2 in culture than did ihymocytes from conirol mice. A small but significant reduction in the population of ceils bearing neither CD4 nor CD8 surface markers ('double negatives') was observed in ihe androgen-resistani mice. These data indicate that androgen resistance is associated in the Tfm/Y mouse wilh alterations in ihymocyte number, phenotype. and function that may be attributable to lack of androgen action during ihymic development.
Androgens Accelerate Thymocyte Apoptosis 1
Endocrinology, 1998
Mechanisms of androgen-induced thymic involution are largely undefined. We have found that significant decreases in thymic size occur 2-4 h after a dose of testosterone is administered to castrated male mice. This rapid rate of change suggests a role for androgeninduced apoptosis in modulating the size and composition of the thymus. Using thymic organ cultures to define these effects of androgens, we found that dihydrotestosterone treatment of thymus tissues from females or from castrated males results in enhancement of thymocyte apoptosis. Intact (androgen-replete) or testicular feminization, Tfm/Y (androgen-resistant) mice failed to show apoptotic change with androgen treatment, although the apoptotic response to glucocorticoids was present, suggesting a requirement for a functional androgen receptor. Acceleration of thymocyte apoptosis by androgens may mediate processes of thymocyte selection, with the potential to impart gender-specific characteristics on the peripheral T cell repertoire.
Androgens Accelerate Thymocyte Apoptosis
2010
Mechanisms of androgen-induced thymic involution are largely undefined. We have found that significant decreases in thymic size occur 2-4 h after a dose of testosterone is administered to castrated male mice. This rapid rate of change suggests a role for androgeninduced apoptosis in modulating the size and composition of the thymus. Using thymic organ cultures to define these effects of androgens, we found that dihydrotestosterone treatment of thymus tissues from females or from castrated males results in enhancement of thymocyte apoptosis. Intact (androgen-replete) or testicular feminization, Tfm/Y (androgen-resistant) mice failed to show apoptotic change with androgen treatment, although the apoptotic response to glucocorticoids was present, suggesting a requirement for a functional androgen receptor. Acceleration of thymocyte apoptosis by androgens may mediate processes of thymocyte selection, with the potential to impart gender-specific characteristics on the peripheral T cell repertoire.
Immunochemical and flow cytometric analysis of androgen receptor expression in thymocytes
Molecular and Cellular Endocrinology, 1995
A variety of evidence suggests that the cells of the immune system are targets for the actions of gonadal steroids. Experiments in both normal animals and in autoimmune disease models have established that androgens exert immunomodulatory effects at the level of the thymus. We have attempted to define precisely the potential target cells for androgen action in the thymus using recently developed antibodies to the androgen receptor. We report here that these antibodies reveal AR expression in all classes of thymocytes defined by surface markers CD4 and CDS. The highest levels of AR expression were observed in the CD4_CD8+ and CD4%D8-subsets that include the most immature cells. These experiments establish that thymocytes are potential targets for direct actions of androgens. The data further suggest AR expression in thymocytes may be developmentally regulated in these cells, and that androgen effects early in the process of thymocyte selection may contribute to the sexual dimorphism of immune responsiveness.
Estrogen Receptor α Is Necessary in Thymic Development and Estradiol-Induced Thymic Alterations
The Journal of Immunology
Estrogens affect the development, maturation, and function of multiple organ systems, including the immune system. One of the main targets of estrogens in the immune system is the thymus, which undergoes atrophy and phenotypic alterations when exposed to elevated levels of estrogen. To determine how estrogens influence the thymus and affect T cell development, estrogen receptor alpha (ERalpha) knockout (ERKO) mice were examined. ERKO mice have significantly smaller thymi than their wild-type (WT) littermates. Construction of ER radiation bone marrow chimeras indicated that the smaller thymi were due to a lack of ERalpha in radiation-resistant tissues rather than hemopoietic elements. ERKO mice were also susceptible to estradiol-induced thymic atrophy, but the extent of their atrophy was less than what was seen in WT mice. The estradiol-treated ERKO mice failed, however, to manifest alterations in their thymic CD4/CD8 phenotypes compared with WT mice. Therefore, ERalpha is essential ...
Evidence that androgens modulate human thymic T cell output
Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 2011
The thymus has long been recognized as a target for the actions of androgenic hormones, but it has only been recently recognized that alterations in circulating levels of gonadal steroids might affect thymic output of T cells. We had the opportunity to examine parameters of thymic cellular output in several hypogonadal men undergoing androgen replacement therapy. Circulating naive (CD4+CD45RA+) T cells were quantitated by flow cytometric analysis of peripheral blood mononuclear cells. Cells bearing T-cell receptor excision circles were quantitated using real-time polymerase chain reaction amplification of DNA isolated from peripheral blood mononuclear cells from healthy men and from hypogonadal men before and after testosterone replacement therapy. CD4+CD45+ (naive) T cells comprised 10.5% of lymphocytes in healthy males; this proportion was greatly increased in 2 hypogonadal men (35.5% and 44.4%). One man was studied sequentially during treatment with physiologic doses of testoster...
Endocrine, 2000
Estrogen receptors (ERs) are expressed in the thymus of both males and females, but their role in thymic development and function is unclear. To determine whether ER plays a role in thymic function of either males or females, we compared thymuses of male and female wild-type (WT) and ER knockout ( ERKO) mice from birth to adulthood. Although thymic size was similar in both male and female WT and ERKO mice at birth (d 0), by postnatal d 5 and at all subsequent ages, both male and female ERKO mice had significant (30-55%) reductions in thymic weight. Morphometric analysis revealed a reduction in thymic medullary areas in adult ERKO mice compared with age-matched WT controls that paralleled thymic involution. There were changes in relative percentages of CD4 + and CD4 + CD8 + T-cells, and large decreases (70-80%) in overall absolute numbers of CD4 + and CD4 + CD8 + T-cells. Serum corticosterone and testosterone levels were not different in either neonatal or adult male WT or ERKO mice, and serum levels of 17 -estradiol (E 2 ) were similar in neonatal WT and ERKO males, indicating that increases in these thymolytic hormones are not responsible for the decreased thymic weight in ERKO males. Additionally, delayed-type hypersensitivity was significantly increased in male ERKO mice compared with WT mice. In summary, ER deficiency does not inhibit initial differentiation or fetal thymic development, but the absence of ER results in marked decreases in thymic size in both sexes during the postnatal period. These results are the first direct demonstration that the E 2 /ER signaling system is necessary for maintenance of normal postnatal function of the female thymus gland. The similar results obtained in males demonstrate a role for the E 2 /ER signaling system in the male thymus and emphasize that estrogens play a more critical role in the male than previously realized.
Endocrine, 2000
Estrogen receptors (ERs) are expressed in the thymus of both males and females, but their role in thymic development and function is unclear. To determine whether ER plays a role in thymic function of either males or females, we compared thymuses of male and female wild-type (WT) and ER knockout ( ERKO) mice from birth to adulthood. Although thymic size was similar in both male and female WT and ERKO mice at birth (d 0), by postnatal d 5 and at all subsequent ages, both male and female ERKO mice had significant (30-55%) reductions in thymic weight. Morphometric analysis revealed a reduction in thymic medullary areas in adult ERKO mice compared with age-matched WT controls that paralleled thymic involution. There were changes in relative percentages of CD4 + and CD4 + CD8 + T-cells, and large decreases (70-80%) in overall absolute numbers of CD4 + and CD4 + CD8 + T-cells. Serum corticosterone and testosterone levels were not different in either neonatal or adult male WT or ERKO mice, and serum levels of 17 -estradiol (E 2 ) were similar in neonatal WT and ERKO males, indicating that increases in these thymolytic hormones are not responsible for the decreased thymic weight in ERKO males. Additionally, delayed-type hypersensitivity was significantly increased in male ERKO mice compared with WT mice. In summary, ER deficiency does not inhibit initial differentiation or fetal thymic development, but the absence of ER results in marked decreases in thymic size in both sexes during the postnatal period. These results are the first direct demonstration that the E 2 /ER signaling system is necessary for maintenance of normal postnatal function of the female thymus gland. The similar results obtained in males demonstrate a role for the E 2 /ER signaling system in the male thymus and emphasize that estrogens play a more critical role in the male than previously realized.