Sexual Dimorphism in the Immune System Develops in the Perinatal Period

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 834-867-Islet Biology
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-862
Lisa Ma1, Mrinal Ghosh1, Riva Dill1, Arthur P Arnold2, H. Konrad Muller3 and Ameae M Walker*4
1University of California, Riverside, CA, 2Univ of California, Los Angeles, Los Angeles, CA, 3Univeristy of Tasmania, Hobart, Australia, 4Univ of California, Riverside, CA
We have used four core genotype (FCG) mice to determine the relative contributions of gonadal hormones and chromosomal complement to development of immune sexual dimorphism. In FCG mice, the testis-determining gene, Sry, has been moved from the Y chromosome to an autosome. The Y- chromosome and the Sry transgene segregate independently. Thus, mating XY-Sry+ males (M) with XX females (F) yields four genotypes: XXF, XYF (both with ovaries), XXM and XYM (both with testes).  At 1 day of age, XXM had half the number of CD4+ and CD8+ cells in the thymus versus the other genotypes, indicating a combined chromosomal and gonadal effect on prenatal development. Use of flutamide (Flu) to block the portion of the perinatal surge of testosterone (T) that occurs in M prior to parturition, normalized numbers of thymic CD8+ in XXM and boosted numbers and exit to the spleen in XYM, while having no effect on F CD8+. Thus, specific negative effects on CD8+ are dictated by pup T. By contrast, Flu treatment decreased CD4+ cells in the thymus, and these and CD19+ (B cells) in the spleen in all genotypes, suggesting a concurrent effect on an early lymphopoietic precursor via endocrine changes in the dam. By 1 week of age, there was pronounced sexual dimorphism in the spleen with 6 fold the number of CD8+ and 3 fold the number of CD4+ in F versus M. For CD8+ cells, the difference reflected no change in number from day 1 in males, but an increase in females, whereas for CD4+ there were differential increases over day 1. There were no differences in hematopoietic and thymopoietic precursors in the spleen, but twice as many precursors in the thymus in M, consistent with delayed maturation and the reduced output of mature thymocytes. Flu treatment of pups between 1 and 7 days reduced the number of CD4+ and CD8+ cells only in the thymus and only in males, with no effect on CD19+. In adult mice, gonadectomized at 10 weeks and examined at 14 weeks, the same sexual dimorphism was observed, with XYF and XXF having a larger number of CD8+ (6 fold) and CD4+ (2 fold) than either M genotype in the spleen, and a higher percentage of CD8hi and CD4+ in blood. Relative to other genotypes, XXM had 50% fewer CD8+ in thymus and 50% fewer CD4+ plus CD8+ cells in thymus+spleen, again illustrating the XX versus. XY difference in M thymocyte production. An examination of the numbers of Tregulatory cells (Tregs) in both the spleen and thymus showed no differences among the genotypes, but because the numbers of effector cells are so different, the ratio of Tregs to effector cells is consistent with less robust immune responses in males. We conclude that there are both chromosomal and gonadal influences on thymocyte production, that substantial immune sexual dimorphism develops by week 1, and that less robust immune responses in males can be attributed in large part to both the relative number of effector cells and the ratio of these to Tregs.

Nothing to Disclose: LM, MG, RD, APA, HKM, AMW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development #065099 awarded to AMW.