The SJL strain of mice has a known dimorphism in the immune response, with females having more robust cytokine production than males. Mice which differ in the complement of sex chromosomes, while having the same gonadal type, have been created and backcrossed onto the SJL strain to determine the effect of sex chromosomes on immune responses in the absence of confounding effects of exposure to different types of adult or developmental sex hormones. Surprisingly, we found that the male XY genotype is relatively stimulatory, while the male sex hormone (testosterone) is inhibitory, for cytokine production of lymph node cells (LNCs) from SJL mice immunized with the autoantigen myelin basic protein (MBP). This is the first experimental evidence of a compensatory effect of sex chromosomes and sex hormones on a biologic process. In aim #1 of this proposal, we will determine whether other key immune parameters, in addition to cytokine production, are also influenced by sex chromosome genotype. In aim #2, we will ascertain whether sex chromosome genotype does or does not influence immune responses in a strain not characterized by greater immune responses in females as compared to males, the C57BL/6. Finally, in aim #3, we will determine if the sex chromosome effect on immune responses is attributed to the dose of X or Y genes. Together these proposed studies will greatly advance the understanding of the role of sex chromosomes on immune responses.