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Neonatal B Cells Suppress Innate Toll-Like Receptor Immune Responses and Modulate Alloimmunity¹

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520

It has been known for decades that neonates are susceptible to transplant tolerance, but the immunological mechanisms involved remain to be fully elucidated. Recent evidence indicates that the maturation state of DCs responding to an allograft may have a profound impact on whether immunity or tolerance ensues. Given that TLR activation is a key process leading to DC maturation, we hypothesized that DCs from neonates have defective TLR immune responses. Contrary to our hypothesis, we found that murine neonatal DCs demonstrated enhanced TLR responses in comparison to adult counterparts in vitro. However, we found that neonatal B cells possess unique immunoregulatory functions as they impaired DC responses to TLR activation in an IL-10-dependent fashion. Functionally, we demonstrated that TLR-activated neonatal, but not adult, B cells impaired Th1, but not Th2, T cell alloimmune responses in vitro and in vivo, in models of alloimmune priming and allotransplantation. We conclude that neonatal B cells possess unique immunoregulatory properties that inhibit DC function and modulate alloimmunity in our murine experimental systems.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Roche Organ Transplant Research Foundation (29991650 and 86166890) and in part from National Institutes of Health Grant R01 AI064660 awarded to D.R.G.

² Address correspondence and reprint requests to Dr. Daniel R. Goldstein, The Anlyan Center S469, 333 Cedar Street, 3FMP, New Haven, CT, 06520. E-mail address: daniel.goldstein{at}yale.edu

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; WT, wild type; MHCII, MHC class II.