Since enteric microbial composition is a distinctive and stable individual trait, microbial heterogeneity may confer lifelong, non-genetic differences between individuals. Here we report that C57BL/6 mice bearing restricted flora microbiota, a distinct but diverse resident enteric microbial community, are numerically and functionally deficient in marginal zone (MZ) B cells. Surprisingly, MZ B-cell levels are minimally affected by germ-free conditions or null mutations of various TLR signaling molecules. In contrast, MZ B-cell depletion is exquisitely dependent on cytolytic CD81 T cells, and includes targeting of a cross-reactive microbial/endogenous MHC class 1B antigen. Thus, members of certain enteric microbial communities link with CD8 1 T cells as a previously unappreciated mechanism that shapes innate immunity dependent on innate-like B cells.Key words: Animal models . B-cell development . CD8 T cells . Enteric microbiota
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IntroductionThe enteric microbial community is astonishingly abundant and diverse in composition [1,2]. Acquired during infancy, typically of maternal origin, its composition becomes a unique but stable trait of each individual throughout life [3]. Due to its abundance, diversity, and unculturability, there is much to learn about the functionalities and impact of the enteric microbial community on host biology. Since its composition is a distinguishing trait of each individual, it represents a potentially important epigenetic factor that may shape each individual's physiology and disease susceptibility [4]. The immune system is predicted to be a key target of these epigenetic forces, since it is highly specialized both for microbial sensing and for alterations in these signals.The innate-like and adaptive arms of the immune system have emerged as a framework for the cellular processes of Eur. J. Immunol. 2008. 38: 3411-3425 DOI 10.1002 Immunomodulation 3411 microbial defense and immunoregulation [5], recently illustrated by the reciprocal roles of dendritic cells in the composition of the enteric microbiota and its contribution to colitis susceptibility [6]. Innate-like functions are associated with the MZ and B-1 B-cell subsets [7,8], which emerge from post-medullary stages of B-cell differentiation. Although conventional follicular mature (FM) B cells function in adaptive B-lymphocyte responses, marginal zone (MZ) and B-1a B cells function in early T-independent (TI) IgM antibody responses, display elevated responsiveness through TLR, and have a limited capacity for immunologic memory [9]. The present study addresses the role of TLR responsiveness, and other modes of enteric microbial sensing, on the levels of MZ B cells in the periphery. We report three observations on the role of endogenous microbial flora in the fate of this B-cell population. First, we demonstrate that mice colonized with distinct communities of resident bacteria exhibit striking defects in innate-like B-cell populations in the spleen and body cavities respectively). Second, ...