Innate immune signaling by the intestinal flora susceptibility to food allergy

The involvement of the intestinal commensal flora in the regulation of immune responsiveness is gaining increasing attention. Work from our laboratory has shown that mice that are unable to signal via TLR4, the receptor for bacterial LPS, are highly susceptible to an allergic response to food. Intragastric administration of a food allergen with the mucosal adjuvant cholera toxin induces allergen specific IgE, elevated plasma histamine levels and anaphylactic symptoms in TLR4 mutant, but not TLR4 wild type, mice. Susceptibility to allergy correlates with a Th2 biased cytokine response in both mucosal (mesenteric lymph node, MLN, and Peyer's patch) and systemic (spleen) tissues of TLR4 mutant mice. When the composition of the bacterial flora is reduced and altered by antibiotic administration (beginning at two weeks of age) TLR4 wild type mice become as susceptible to the induction of allergy as their TLR4 mutant counterparts. Both allergen specific IgE and Th2 cytokine responses are reduced in antibiotic treated mice in which the flora has been allowed to repopulate. In more recent work we have shown that, in TLR4 wild type mice, a putative regulatory population of plasmacytoid DC (pDC), with constitutive expression of IL-10, is detectable in the MLN (which drains the gut associated lymphoid tissue) but not the spleen. The constitutive expression of both IL-10 and IL-6 mRNA by this pDC population is impaired in TLR4 mutant mice. Indeed, antibiotic decontamination of the gut eliminates the constitutive expression of IL-10 and IL-6 by MLN pDC, further supporting for a role for the flora in stimulating the expression of these cytokines. Moreover, the immunoregulatory function of IL-10 secreting Tregs is also defective in TLR4 mutant mice. Taken together these observations have led us to hypothesize that TLR4 mutant mice are highly susceptible to allergic responses to food antigens because they lack a population of regulatory T cells, induced by the commensal flora, which is present in wild type mice.