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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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Identification of SFBNYU_004990 epitopes recognized by related TCRs(a) Top: The distribution in Th17 and non-Th17 cells of four TCRs that share an identical TCRα chain. Bottom: Amino acid alignment of the Vβ14 CDR3 sequences. The green box highlights the sequence differences. (b) Stimulation of the 5A11 hybridoma by bacterial pool 2D10 in the SFB antigen screen. (c) Responses of 4 TCR hybridomas, including a non-Th17 hybridoma, to bacterial clone 2D10-A10. (d) Responses of the 2D10-A10-specific TCR hybridomas to core epitopes encoded by minigenes expressed in E.coli. (e) TCR hybridoma responses to titrated synthetic peptide (IRWFGSSVQKV) in the presence of APCs.
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Figure 6: Identification of SFBNYU_004990 epitopes recognized by related TCRs(a) Top: The distribution in Th17 and non-Th17 cells of four TCRs that share an identical TCRα chain. Bottom: Amino acid alignment of the Vβ14 CDR3 sequences. The green box highlights the sequence differences. (b) Stimulation of the 5A11 hybridoma by bacterial pool 2D10 in the SFB antigen screen. (c) Responses of 4 TCR hybridomas, including a non-Th17 hybridoma, to bacterial clone 2D10-A10. (d) Responses of the 2D10-A10-specific TCR hybridomas to core epitopes encoded by minigenes expressed in E.coli. (e) TCR hybridoma responses to titrated synthetic peptide (IRWFGSSVQKV) in the presence of APCs.

Mentions: Another expression screen was performed using the 1A7 hybridoma, which along with three other TCRs formed a distinct cluster with an identical Vα and highly similar Vβ14 CDR3 sequences (Extended Data Fig. 6a). A stimulatory clone, designated 2D10-A10 (Extended Data Fig. 6b & c), contained the N-terminal sequence of another SFB gene (SFBNYU_00499019). We mapped the epitope for the 1A7 hybridoma to 9 amino acids (Extended Data Fig. 6d). Both the full-length gene product and a 9 amino acid peptide stimulated all four TCRs, indicating that these TCRs indeed recognize the same epitope (Fig. 2b, right). However, the single TCR derived from non-Th17 cells (3F4) displayed a much weaker dose-response to peptide antigen than the other TCRs (Extended Data Fig. 6e).


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)

Identification of SFBNYU_004990 epitopes recognized by related TCRs(a) Top: The distribution in Th17 and non-Th17 cells of four TCRs that share an identical TCRα chain. Bottom: Amino acid alignment of the Vβ14 CDR3 sequences. The green box highlights the sequence differences. (b) Stimulation of the 5A11 hybridoma by bacterial pool 2D10 in the SFB antigen screen. (c) Responses of 4 TCR hybridomas, including a non-Th17 hybridoma, to bacterial clone 2D10-A10. (d) Responses of the 2D10-A10-specific TCR hybridomas to core epitopes encoded by minigenes expressed in E.coli. (e) TCR hybridoma responses to titrated synthetic peptide (IRWFGSSVQKV) in the presence of APCs.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: Identification of SFBNYU_004990 epitopes recognized by related TCRs(a) Top: The distribution in Th17 and non-Th17 cells of four TCRs that share an identical TCRα chain. Bottom: Amino acid alignment of the Vβ14 CDR3 sequences. The green box highlights the sequence differences. (b) Stimulation of the 5A11 hybridoma by bacterial pool 2D10 in the SFB antigen screen. (c) Responses of 4 TCR hybridomas, including a non-Th17 hybridoma, to bacterial clone 2D10-A10. (d) Responses of the 2D10-A10-specific TCR hybridomas to core epitopes encoded by minigenes expressed in E.coli. (e) TCR hybridoma responses to titrated synthetic peptide (IRWFGSSVQKV) in the presence of APCs.
Mentions: Another expression screen was performed using the 1A7 hybridoma, which along with three other TCRs formed a distinct cluster with an identical Vα and highly similar Vβ14 CDR3 sequences (Extended Data Fig. 6a). A stimulatory clone, designated 2D10-A10 (Extended Data Fig. 6b & c), contained the N-terminal sequence of another SFB gene (SFBNYU_00499019). We mapped the epitope for the 1A7 hybridoma to 9 amino acids (Extended Data Fig. 6d). Both the full-length gene product and a 9 amino acid peptide stimulated all four TCRs, indicating that these TCRs indeed recognize the same epitope (Fig. 2b, right). However, the single TCR derived from non-Th17 cells (3F4) displayed a much weaker dose-response to peptide antigen than the other TCRs (Extended Data Fig. 6e).

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