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TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease.

Pappu BP, Borodovsky A, Zheng TS, Yang X, Wu P, Dong X, Weng S, Browning B, Scott ML, Ma L, Su L, Tian Q, Schneider P, Flavell RA, Dong C, Burkly LC - J. Exp. Med. (2008)

Bottom Line: Consistent with these data, TL1A(-/-) animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE).Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells.These observations thus establish an important role of the TL1A-DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT
T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A-DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A(-/-) dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A(-/-) animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A-DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease.

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DR3 expression is greatly enhanced in Th17 cells. Naive OT-II cells were differentiated and DR3 expression was analyzed by real-time PCR analysis. DR3 expression was determined relative to naive CD4+ T cell expression levels and normalized to GAPDH levels in all samples. (A) Comparison of DR3 expression on CD4+ cells differentiated under Th1, Th2, and Th17 conditions. (B) Time-course analysis of DR3 expression in CD4+ T cells differentiating under Th17 conditions. (C) Analysis of DR3 expression in cells differentiated under different combinations of cytokines. Primers used in A–C detect all DR3 isoforms. (D) Analysis of the full-length transmembrane-containing DR3 isoform (variant 1) in Th17 and T reg cells. (E) The ratio of total transmembrane DR3 (variants 1 and 3 combined) and full-length transmembrane DR3 (variant 1) was measured in Th17 and T reg cells. Error bars represent SD.
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fig1: DR3 expression is greatly enhanced in Th17 cells. Naive OT-II cells were differentiated and DR3 expression was analyzed by real-time PCR analysis. DR3 expression was determined relative to naive CD4+ T cell expression levels and normalized to GAPDH levels in all samples. (A) Comparison of DR3 expression on CD4+ cells differentiated under Th1, Th2, and Th17 conditions. (B) Time-course analysis of DR3 expression in CD4+ T cells differentiating under Th17 conditions. (C) Analysis of DR3 expression in cells differentiated under different combinations of cytokines. Primers used in A–C detect all DR3 isoforms. (D) Analysis of the full-length transmembrane-containing DR3 isoform (variant 1) in Th17 and T reg cells. (E) The ratio of total transmembrane DR3 (variants 1 and 3 combined) and full-length transmembrane DR3 (variant 1) was measured in Th17 and T reg cells. Error bars represent SD.

Mentions: Although considerable progress has been made in identifying the various cytokines and transcriptional factors critical for Th17 differentiation, molecular pathways selectively regulating the expansion and function of this important Th subset remain unclear. To address this, we analyzed gene expression profiles by microarray analysis of Th1, Th2, and Th17 effector cells and discovered that expression of DR3 (TNFRSF25), which binds to TNF family member TL1A, was significantly enhanced in Th17 cells when compared with the other two Th subsets (unpublished data). Because TNF family members regulate cell proliferation and survival, this result suggests the possibility that DR3–TL1A interaction may be involved in the regulation of Th17 cells. To further confirm this observation, CD4+ T cells from OT-II TCR transgenic mice were differentiated under Th1, Th2, or Th17 conditions, and mRNA was prepared on day 5 after restimulation and analyzed for DR3 expression by real-time PCR analysis. As shown in Fig. 1 A, total DR3 expression was greatly increased in the Th17 subset compared with Th1 and Th2 cells, using a primer pair that allows detection of all DR3 isoforms. Furthermore, DR3 expression was not detected during the first 2 d of differentiation but was up-regulated by day 5 (Fig. 1 B), suggesting that DR3 up-regulation occurs at a later stage of Th17 differentiation.


TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease.

Pappu BP, Borodovsky A, Zheng TS, Yang X, Wu P, Dong X, Weng S, Browning B, Scott ML, Ma L, Su L, Tian Q, Schneider P, Flavell RA, Dong C, Burkly LC - J. Exp. Med. (2008)

DR3 expression is greatly enhanced in Th17 cells. Naive OT-II cells were differentiated and DR3 expression was analyzed by real-time PCR analysis. DR3 expression was determined relative to naive CD4+ T cell expression levels and normalized to GAPDH levels in all samples. (A) Comparison of DR3 expression on CD4+ cells differentiated under Th1, Th2, and Th17 conditions. (B) Time-course analysis of DR3 expression in CD4+ T cells differentiating under Th17 conditions. (C) Analysis of DR3 expression in cells differentiated under different combinations of cytokines. Primers used in A–C detect all DR3 isoforms. (D) Analysis of the full-length transmembrane-containing DR3 isoform (variant 1) in Th17 and T reg cells. (E) The ratio of total transmembrane DR3 (variants 1 and 3 combined) and full-length transmembrane DR3 (variant 1) was measured in Th17 and T reg cells. Error bars represent SD.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2373838&req=5

fig1: DR3 expression is greatly enhanced in Th17 cells. Naive OT-II cells were differentiated and DR3 expression was analyzed by real-time PCR analysis. DR3 expression was determined relative to naive CD4+ T cell expression levels and normalized to GAPDH levels in all samples. (A) Comparison of DR3 expression on CD4+ cells differentiated under Th1, Th2, and Th17 conditions. (B) Time-course analysis of DR3 expression in CD4+ T cells differentiating under Th17 conditions. (C) Analysis of DR3 expression in cells differentiated under different combinations of cytokines. Primers used in A–C detect all DR3 isoforms. (D) Analysis of the full-length transmembrane-containing DR3 isoform (variant 1) in Th17 and T reg cells. (E) The ratio of total transmembrane DR3 (variants 1 and 3 combined) and full-length transmembrane DR3 (variant 1) was measured in Th17 and T reg cells. Error bars represent SD.
Mentions: Although considerable progress has been made in identifying the various cytokines and transcriptional factors critical for Th17 differentiation, molecular pathways selectively regulating the expansion and function of this important Th subset remain unclear. To address this, we analyzed gene expression profiles by microarray analysis of Th1, Th2, and Th17 effector cells and discovered that expression of DR3 (TNFRSF25), which binds to TNF family member TL1A, was significantly enhanced in Th17 cells when compared with the other two Th subsets (unpublished data). Because TNF family members regulate cell proliferation and survival, this result suggests the possibility that DR3–TL1A interaction may be involved in the regulation of Th17 cells. To further confirm this observation, CD4+ T cells from OT-II TCR transgenic mice were differentiated under Th1, Th2, or Th17 conditions, and mRNA was prepared on day 5 after restimulation and analyzed for DR3 expression by real-time PCR analysis. As shown in Fig. 1 A, total DR3 expression was greatly increased in the Th17 subset compared with Th1 and Th2 cells, using a primer pair that allows detection of all DR3 isoforms. Furthermore, DR3 expression was not detected during the first 2 d of differentiation but was up-regulated by day 5 (Fig. 1 B), suggesting that DR3 up-regulation occurs at a later stage of Th17 differentiation.

Bottom Line: Consistent with these data, TL1A(-/-) animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE).Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells.These observations thus establish an important role of the TL1A-DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT
T helper type 17 (Th17) cells play an important pathogenic function in autoimmune diseases; their regulation, however, is not well understood. We show that the expression of a tumor necrosis factor receptor family member, death receptor 3 (DR3; also known as TNFRSF25), is selectively elevated in Th17 cells, and that TL1A, its cognate ligand, can promote the proliferation of effector Th17 cells. To further investigate the role of the TL1A-DR3 pathway in Th17 regulation, we generated a TL1A-deficient mouse and found that TL1A(-/-) dendritic cells exhibited a reduced capacity in supporting Th17 differentiation and proliferation. Consistent with these data, TL1A(-/-) animals displayed decreased clinical severity in experimental autoimmune encephalomyelitis (EAE). Finally, we demonstrated that during EAE disease progression, TL1A was required for the optimal differentiation as well as effector function of Th17 cells. These observations thus establish an important role of the TL1A-DR3 pathway in promoting Th17 cell function and Th17-mediated autoimmune disease.

Show MeSH
Related in: MedlinePlus