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Focused specificity of intestinal TH17 cells towards commensal bacterial antigens.

Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M, Linehan JL, Alonzo F, Ng C, Chen A, Lin X, Sczesnak A, Liao JJ, Torres VJ, Jenkins MK, Lafaille JJ, Littman DR - Nature (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.

ABSTRACT
T-helper-17 (TH17) cells have critical roles in mucosal defence and in autoimmune disease pathogenesis. They are most abundant in the small intestine lamina propria, where their presence requires colonization of mice with microbiota. Segmented filamentous bacteria (SFB) are sufficient to induce TH17 cells and to promote TH17-dependent autoimmune disease in animal models. 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 antigen 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 harboured 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.

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SFB-specific Th17 cells are present in both SILP and LILP of SFB-colonized miceT cells were stained with I-Ab/3340-A6 tetramer and antibody to intracellular RORγt. (a) Representative FACS plots (gated on CD4+ T cells). (b) Analysis of multiple animals. Left: percent of tetramer-positive cells among total CD4+ T cells in each region of the intestine. Right: percent of RORγt+ cells among the tetramer-positive cells. Each symbol represents cells from a separate animal.
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Figure 10: SFB-specific Th17 cells are present in both SILP and LILP of SFB-colonized miceT cells were stained with I-Ab/3340-A6 tetramer and antibody to intracellular RORγt. (a) Representative FACS plots (gated on CD4+ T cells). (b) Analysis of multiple animals. Left: percent of tetramer-positive cells among total CD4+ T cells in each region of the intestine. Right: percent of RORγt+ cells among the tetramer-positive cells. Each symbol represents cells from a separate animal.

Mentions: SFB colonization of the small intestine is potentially beneficial, attenuating pathogenic bacteria-induced colitis 8, but it can also trigger or exacerbate systemic autoimmune disease 10,11, raising the question as to whether SFB-specific Th17 cells can circulate beyond the small intestine. We examined the colons and spleens of SFB-positive recipients of 7B8Tg naïve T cells, and found these cells in both organs. Importantly, more than 80% of these SFB-specific T cells in colon and 40% in spleen expressed RORγt (Fig. 4b). Consistent with this result, staining of endogenous T cells from Tac mice revealed 3340-A6 tetramer-positive cells in the large intestine and most of these cells expressed RORγt (Extended Data Fig. 10a and b).


Focused specificity of intestinal TH17 cells towards commensal bacterial antigens.

Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M, Linehan JL, Alonzo F, Ng C, Chen A, Lin X, Sczesnak A, Liao JJ, Torres VJ, Jenkins MK, Lafaille JJ, Littman DR - Nature (2014)

SFB-specific Th17 cells are present in both SILP and LILP of SFB-colonized miceT cells were stained with I-Ab/3340-A6 tetramer and antibody to intracellular RORγt. (a) Representative FACS plots (gated on CD4+ T cells). (b) Analysis of multiple animals. Left: percent of tetramer-positive cells among total CD4+ T cells in each region of the intestine. Right: percent of RORγt+ cells among the tetramer-positive cells. Each symbol represents cells from a separate animal.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4128479&req=5

Figure 10: SFB-specific Th17 cells are present in both SILP and LILP of SFB-colonized miceT cells were stained with I-Ab/3340-A6 tetramer and antibody to intracellular RORγt. (a) Representative FACS plots (gated on CD4+ T cells). (b) Analysis of multiple animals. Left: percent of tetramer-positive cells among total CD4+ T cells in each region of the intestine. Right: percent of RORγt+ cells among the tetramer-positive cells. Each symbol represents cells from a separate animal.
Mentions: SFB colonization of the small intestine is potentially beneficial, attenuating pathogenic bacteria-induced colitis 8, but it can also trigger or exacerbate systemic autoimmune disease 10,11, raising the question as to whether SFB-specific Th17 cells can circulate beyond the small intestine. We examined the colons and spleens of SFB-positive recipients of 7B8Tg naïve T cells, and found these cells in both organs. Importantly, more than 80% of these SFB-specific T cells in colon and 40% in spleen expressed RORγt (Fig. 4b). Consistent with this result, staining of endogenous T cells from Tac mice revealed 3340-A6 tetramer-positive cells in the large intestine and most of these cells expressed RORγt (Extended Data Fig. 10a and b).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.

ABSTRACT
T-helper-17 (TH17) cells have critical roles in mucosal defence and in autoimmune disease pathogenesis. They are most abundant in the small intestine lamina propria, where their presence requires colonization of mice with microbiota. Segmented filamentous bacteria (SFB) are sufficient to induce TH17 cells and to promote TH17-dependent autoimmune disease in animal models. 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 antigen 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 harboured 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.

Show MeSH
Related in: MedlinePlus