Basic—Alimentary TractToll-Like Receptor Signaling in Small Intestinal Epithelium Promotes B-Cell Recruitment and IgA Production in Lamina Propria
Section snippets
Mice
Plasmids containing the mouse villin promoter (pBS-Villin)21 and mCD4-hTLR4 fusion gene have been previously described.22 The mCD4-hTLR4 was polymerase chain reaction (PCR) amplified and cloned into pBS-Villin. The sequences were verified by sequencing. The transgene was gel purified, microinjected into fertilized eggs from [C57BL/6J × DBA/2]F2 mice, and the eggs transferred into oviducts of ICR foster mothers. Identification of the transgenic mice was done by PCR amplification using the
Generation of Transgenic Mice Expressing mCD4-hTLR4
To study the biologic effects of TLR signaling in the intestinal epithelium in vivo, we generated transgenic mice expressing a constitutively active form of TLR4 on IECs. The mice carry an mCD4-hTLR4 transgene that consists of the human TLR4 transmembrane and intracellular domains fused to the extracellular domain of murine CD4. This construct has been shown to signal similarly to endogenous TLR4 both in vitro and in vivo.22, 26 The transgene was driven by the villin promoter (Figure 1A), which
Discussion
Here, we report that increased activation of the TLR signaling in IECs induces a remarkable and unsuspected phenotype: the accumulation of large numbers of B cells and IgA+ cells in the intestine. This response reveals an important role for the IEC compartment in response to environmental signals and suggests a novel mechanism for maintenance of intestinal homeostasis. By mediating an increase in luminal IgA in response to TLR activation, IECs may prevent attachment and possibly invasion of
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Supported by NIH grants P01 DK072201 (to S.A.L. and L.M.), AI052266 (to M.T.A.), and DK069594 (to M.T.A.); Career Development Award from CCFA (to M.F.); Uehara Memorial Foundation Research Fellowship (to M.F.); New York Crohn's Foundation and CCFA (to L.M.).
Conflicts of interest: There are no conflicts of interest to disclose.