Focused specificity of intestinal TH17 cells towards commensal bacterial antigens

Abstract

T-helper-17 (Th17) cells have critical roles in mucosal defense and in autoimmune disease pathogenesis 1-3. They are most abundant in the small intestine lamina propria (SILP), where their presence requires colonization of mice with microbiota 4-7. Segmented Filamentous Bacteria (SFB) are sufficient to induce Th17 cells and to promote Th17-dependent autoimmune disease in animal models 8-14. However, the specificity of Th17 cells, the mechanism of their induction by distinct bacteria, and the means by which they foster tissue-specific inflammation remain unknown. Here we show that the T cell receptor (TCR) repertoire of intestinal Th17 cells in SFB-colonized mice has minimal overlap with that of other intestinal CD4+ T cells and that most Th17 cells, but not other T cells, recognize antigens encoded by SFB. T cells with antigen receptors specific for SFB-encoded peptides differentiated into RORγt-expressing Th17 cells, even if SFB-colonized mice also harbored a strong Th1 cell inducer, Listeria monocytogenes, in their intestine. The match of T cell effector function with antigen specificity is thus determined by the type of bacteria that produce the antigen. These findings have significant implications for understanding how commensal microbiota contribute to organ-specific autoimmunity and for developing novel mucosal vaccines.

Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice

“…Moreover, Th17 cells in SPF mice gavaged with B. adolescentis did not display preferential Vβ14 T-cell receptor (TCR) chain use as exhibited by SFB-specific Th17 cells (Fig. 3D) (35), suggesting that the gut Th17 cells elicited by B. adolescentis and SFB were not recognizing a common immunodominant microbial antigen. Collectively, the data indicate that intestinal Th17 cells induced by B. adolescentis were symbiont-specific.…”

“…Therefore, B. adolescentis seems to be a bona fide intestinal symbiont akin to SFB in mice, capable of peaceful coexistence in the gut of a healthy host, despite its profound impact on the Th17 compartment. Recent studies have shown that gut Th17 cells in SFB-bearing hosts are specific for SFB-derived antigens (34,35). To determine if B. adolescentis-induced intestinal Th17 cells are analogously specific for B. adolescentis, we isolated CD4 + T cells from the small intestine of monocolonized mice and measured their cytokine responses to stimulation by lysates from various bacterial species.…”

Microbiota, regulatory T cell subsets, and allergic disorders

“…Whether 17 cells di erentiated in the intestine do also contribute to asthma exacerbation in the lung is not known. However, a recent report shows that 17 cells from SFB-positive mice contain a T cell receptor repertoire that is essentially speci c to SFB-derived peptides [26]. is nding does not support the possibility that 17 cells primed in the gut in response to SFB colonization exacerbate immune reactions to allergens elsewhere.…”

Microbiote intestinal et développement du système immunitaire

“…Elle induit la production d'IgA et l'activation d'un éventail complet des réponses T, aussi bien pro-inflammatoires que régulatrices [18,22,23]. La colonisation par SFB est en particulier indispensable pour reproduire la stimulation de la réponse TH17 induite par un microbiote complexe [22,23,32]. De façon intéressante, les effets de la SFB sur la maturation des réponses immunes intestinales murines s'accompagnent d'un effet de barrière vis-à-vis de la colonisation par des bactéries pathogènes, non seulement dans l'intestin [30] mais aussi dans les poumons [33].…”