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Humoral Immune Response to Flagellin Requires T Cells and Activation of Innate Immunity¹

Department of Pathology, Emory University, Atlanta, GA 30322

Bacterial flagellin, the primary structural component of flagella, is a dominant target of humoral immunity upon infection by enteric pathogens and in Crohn’s disease. To better understand how such responses may be regulated, we sought to define, in mice, basic mechanisms that regulate generation of flagellin-specific Igs. We observed that, in response to i.p. injection with flagellin, generation of flagellin-specific Ig required activation of innate immunity in that these responses were ablated in MyD88-deficient mice and that flagellin from Helicobacter pylori, which is known not to activate TLR5, also did not elicit Abs. Mice lacking T cells (TCR^null) were completely deficient in their ability to make flagellin Abs in various contexts indicating that, in contrast to common belief, generation of flagellin-specific Ig is absolutely T cell dependent. In contrast to Ab responses to whole flagella (H serotyping), responses to flagellin monomers displayed only moderate serospecificity. Whereas neither oral nor rectal administration of flagellin elicited a strong serum Ab response, induction of colitis with dextran sodium sulfate resulted in a MyD88-dependent serum Ab response to endogenous flagellin, suggesting that, in an inflammatory milieu, TLR signaling promotes acquisition of Abs to intestinal flagellin. Thus, acquisition of a humoral immune response to flagellin requires activation of innate immunity, is T cell dependent, and can originate from flagellin in the intestinal tract in inflammatory conditions in the intestine.

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 the National Institutes of Health via Center Grants to Emory University (DK064399) and University of Alabama (DK64400) and by R-01 Grant DK061417 (to A.T.G.) and via a grant from the Broad Medical Research Program (to A.T.G.).

² Address correspondence and reprint requests to Dr. Andrew T. Gewirtz, Pathology-Whitehead Research Building 105H, 615 Michael Street, Emory University, Atlanta, GA 30322. E-mail address: agewirt{at}emory.edu

³ Abbreviations used in this paper: WT, wild type; DSS, dextran sodium sulfate; DSP, dithiobis (succinimidyl) propionate.

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