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12 p.-7 fig., IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo., This work was supported by grants from the Ministerio de Economía y Competitividad (SAF2014-23801), the Instituto de Salud Carlos III (La Red de Investigación en Inflamación y Enfermedades Reumáticas, RIER RD12/009), and the Comunidad Autónoma de Madrid/FEDER (S2010/BMD-2350, RAPHYME Program) to A.L.C. and M.A.V. and by Instituto de Salud Carlos III Grant PI16/01428 to S.S.-R.

9 p.-5 fig., STUDY QUESTION What role do female sex hormones play in the antisperm immune response?, SUMMARY ANSWER We found that sperm induce a Th17 immune response and that estradiol down-regulates the antisperm Th17 response by dendritic cells., WHAT IS KNOWN ALREADY Estradiol down-regulates the immune response to several pathogens and impairs the triggering of dendritic cell maturation by microbial products., STUDY DESIGN, SIZE, DURATION Ex vivo and in vivo murine models of vaginal infection with sperm and Candida albicans were used to study the induction of Th17 and its hormonal regulation., PARTICIPANTS/MATERIALS, SETTING, METHODS We analyzed the induction of Th17 cytokines and T cells in splenocytes obtained from BALB/c mice challenged with sperm and C. albicans. For the in vivo vaginal infection models, we used ovariectomized mice treated with vehicle, estradiol or progesterone, and we assessed the effect of these hormones on the immune response in the lymph nodes., MAIN RESULTS AND THE ROLE OF CHANCE Th17 cytokines and T cells were induced by sperm antigens in both ex vivo and in vivo experiments. Estrus levels of estradiol down-regulated the Th17 response to sperm and C. albicans in vivo., LIMITATIONS, REASONS FOR CAUTION This study was conducted using murine models; whether or not the results are applicable to humans is not known., WIDER IMPLICATIONS OF THE FINDINGS Our results describe an adaptive mechanism that reconciles immunity and reproduction and further explains why unregulated Th17 could be linked to infertility and recurrent infections., This work was supported by research grants from the Instituto de Salud Carlos III (ISCIII) (PI10/00897) and Fundación Mutua Madrileña to M.R. M.R. holds a Miguel Servet contract from the ISCIII (CP08/00228). M.A.M.-F. was supported by (ISCIII) INTRASALUD PI09/02029.