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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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Th17 TCR repertoire analysis by pyrosequencing(a) Numbers of unique Vβ14 CDR3 sequences of individual SILP Th17 and non-Th17 samples. The sequences were normalized for numbers of cells and total reads. (b) Preferential expansion of Vβ14+ clones in the Th17 compartment in the SILP. The proportions of the 10 most abundant Vβ14 CDR3 sequences from Th17 and non-Th17 cells from 8 mice are shown. (c) Th17-non Th17 bias of unique Vβ14 CDR3 sequences in the SILP of multiple mice.
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Figure 3: Th17 TCR repertoire analysis by pyrosequencing(a) Numbers of unique Vβ14 CDR3 sequences of individual SILP Th17 and non-Th17 samples. The sequences were normalized for numbers of cells and total reads. (b) Preferential expansion of Vβ14+ clones in the Th17 compartment in the SILP. The proportions of the 10 most abundant Vβ14 CDR3 sequences from Th17 and non-Th17 cells from 8 mice are shown. (c) Th17-non Th17 bias of unique Vβ14 CDR3 sequences in the SILP of multiple mice.

Mentions: We chose to focus on Vβ14+ cells to further elucidate the gut CD4+ T cell repertoire. First, we used pyrosequencing to examine the repertoire of Vβ14+ SILP Th17 and non-Th17 cells from SFB-colonized mice. The complementarity determining region 3 (CDR3) of Vβ14 was determined for each cell population from eight Il-23rGFP/+ mice. Each sample contained a minimum of several hundred unique CDR3 sequences (Extended Data Fig. 3a). Interestingly, the ten most frequently used unique CDR3 sequences accounted for 60% of the Th17 and only 40% of the non-Th17 repertoire (Extended Data Fig. 3b). Furthermore, the dominant CDR3 sequences in individual mice exhibited a clear bias towards either Th17 or non-Th17 cells (Supplementary Table 1). Many of these CDR3 sequences were shared between mice and were enriched either in Th17 or in non-Th17 cells in individual mice (Extended Data Fig. 3c).


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)

Th17 TCR repertoire analysis by pyrosequencing(a) Numbers of unique Vβ14 CDR3 sequences of individual SILP Th17 and non-Th17 samples. The sequences were normalized for numbers of cells and total reads. (b) Preferential expansion of Vβ14+ clones in the Th17 compartment in the SILP. The proportions of the 10 most abundant Vβ14 CDR3 sequences from Th17 and non-Th17 cells from 8 mice are shown. (c) Th17-non Th17 bias of unique Vβ14 CDR3 sequences in the SILP of multiple mice.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Th17 TCR repertoire analysis by pyrosequencing(a) Numbers of unique Vβ14 CDR3 sequences of individual SILP Th17 and non-Th17 samples. The sequences were normalized for numbers of cells and total reads. (b) Preferential expansion of Vβ14+ clones in the Th17 compartment in the SILP. The proportions of the 10 most abundant Vβ14 CDR3 sequences from Th17 and non-Th17 cells from 8 mice are shown. (c) Th17-non Th17 bias of unique Vβ14 CDR3 sequences in the SILP of multiple mice.
Mentions: We chose to focus on Vβ14+ cells to further elucidate the gut CD4+ T cell repertoire. First, we used pyrosequencing to examine the repertoire of Vβ14+ SILP Th17 and non-Th17 cells from SFB-colonized mice. The complementarity determining region 3 (CDR3) of Vβ14 was determined for each cell population from eight Il-23rGFP/+ mice. Each sample contained a minimum of several hundred unique CDR3 sequences (Extended Data Fig. 3a). Interestingly, the ten most frequently used unique CDR3 sequences accounted for 60% of the Th17 and only 40% of the non-Th17 repertoire (Extended Data Fig. 3b). Furthermore, the dominant CDR3 sequences in individual mice exhibited a clear bias towards either Th17 or non-Th17 cells (Supplementary Table 1). Many of these CDR3 sequences were shared between mice and were enriched either in Th17 or in non-Th17 cells in individual mice (Extended Data Fig. 3c).

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