Inhibition of Dectin-1 Signaling Ameliorates Colitis by Inducing Lactobacillus-Mediated Regulatory T Cell Expansion in the Intestine

Abstract

Dectin-1, the receptor for β-glucans, protects the host against fungal infection; however, its role in intestinal immunity is incompletely understood. We found that Dectin-1-deficient (Clec7a(-/-)) mice were refractory to both dextran sodium sulfate (DSS)- and CD45RB(high)CD4(+) T cell-induced colitis, and that this resistance was associated with an increase in regulatory T (Treg) cells. The proportion of lactobacilli, especially Lactobacillus murinus, in the commensal microflora was increased in Clec7a(-/-) mouse colons, and accompanied by a decrease in antimicrobial peptides induced by Dectin-1 signaling. L. murinus colonization increased Treg cells in the colon. Oral administration of laminarin, a Dectin-1 antagonist, suppressed the development of DSS-colitis, associated with an increase of L. murinus and Treg cells. Human patients with inflammatory bowel disease were found to have a decreased proportion of closely related Lactobacillus species. These observations suggest that Dectin-1 regulates the homeostasis of intestinal immunity by controlling Treg cell differentiation through modification of microbiota.

Immunity against fungi

“…-/-mice were more resistant to colitis and exhibited a reduction in colonic antimicrobial peptides that target Gram-positive bacteria, leading to an increase in commensal Lactobacillus murinus bacteria, Treg expansion, and resistance to colitis (175). Colonization of Clec7a -/-mice with C. tropicalis reversed these effects and promoted intestinal inflammation.…”

C-type lectin receptors in the control of T helper cell differentiation

“…Although dectin 1-deficient mice are also less resistant to various fungal infections than wild-type mice 25,26 , their level of susceptibility is dependent on the infecting fungal strain, owing to adaptation of fungal cell wall composition in vivo 27 . As shown in mice, dectin 1 is also important for maintaining microbiota homeostasis in the colon by controlling the growth of resident fungi 28 . Dectin 1 recognizes β-glucans that are exposed at the budding scars of pathogenic and opportunistic fungi (TABLE 1).…”

Antigen-specific regulatory T-cell responses to intestinal microbiota

“…For example, IgA responses to bacteria obtained from co-housing with inflammasome-deficient ( Asc −/− ) mice occurred only in T cell-sufficient mice 103 and were specific to Prevotellaceae , Helicobacter sp. flexspira , and SFB–all potential drivers of intestinal inflammation 104-106 . In other studies, two groups observed that SFB 107 and Mucispirillum 108 , both bacteria that tightly adhere to the epithelium, induce TD IgA 102, 103 .…”