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Smad7 in intestinal CD4+ T cells determines autoimmunity in a spontaneous model of multiple sclerosis

Haupeltshofer, Steffen LU ; Leichsenring, Teresa ; Berg, Sarah ; Pedreiturria, Xiomara ; Joachim, Stephanie C. ; Tischoff, Iris ; Otte, Jan Michel ; Bopp, Tobias ; Fantini, Massimo C. and Esser, Charlotte , et al. (2019) In Proceedings of the National Academy of Sciences of the United States of America 116(51). p.25860-25869
Abstract

Environmental triggers acting at the intestinal barrier are thought to contribute to the initiation of autoimmune disorders. The transforming growth factor beta inhibitor Smad7 determines the phenotype of CD4+ T cells. We hypothesized that Smad7 in intestinal CD4+ T cells controls initiation of opticospinal encephalomyelitis (OSE), a murine model of multiple sclerosis (MS), depending on the presence of gut microbiota. Smad7 was overexpressed or deleted in OSE CD4+ T cells to determine the effect on clinical progression, T cell differentiation, and T cell migration from the intestine to the central nervous system (CNS). Smad7 overexpression worsened the clinical course of OSE and increased CNS... (More)

Environmental triggers acting at the intestinal barrier are thought to contribute to the initiation of autoimmune disorders. The transforming growth factor beta inhibitor Smad7 determines the phenotype of CD4+ T cells. We hypothesized that Smad7 in intestinal CD4+ T cells controls initiation of opticospinal encephalomyelitis (OSE), a murine model of multiple sclerosis (MS), depending on the presence of gut microbiota. Smad7 was overexpressed or deleted in OSE CD4+ T cells to determine the effect on clinical progression, T cell differentiation, and T cell migration from the intestine to the central nervous system (CNS). Smad7 overexpression worsened the clinical course of OSE and increased CNS inflammation and demyelination. It favored expansion of intestinal CD4+ T cells toward an inflammatory phenotype and migration of intestinal CD4+ T cells to the CNS. Intestinal biopsies from MS patients revealed decreased transforming growth factor beta signaling with a shift toward inflammatory T cell subtypes. Smad7 in intestinal T cells might represent a valuable therapeutic target for MS to achieve immunologic tolerance in the intestine and suppress CNS inflammation.

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publishing date
type
Contribution to journal
publication status
published
keywords
Gut–brain axis, Multiple sclerosis, Smad7, T helper cell, TGF-beta
in
Proceedings of the National Academy of Sciences of the United States of America
volume
116
issue
51
pages
25860 - 25869
publisher
National Academy of Sciences
external identifiers
  • pmid:31796589
  • scopus:85076684816
ISSN
0027-8424
DOI
10.1073/pnas.1905955116
language
English
LU publication?
no
additional info
Publisher Copyright: © 2019 National Academy of Sciences. All rights reserved.
id
b98c8106-fa50-485a-b9d5-ce1edfb783cb
date added to LUP
2026-02-05 08:57:29
date last changed
2026-02-05 08:58:13
@article{b98c8106-fa50-485a-b9d5-ce1edfb783cb,
  abstract     = {{<p>Environmental triggers acting at the intestinal barrier are thought to contribute to the initiation of autoimmune disorders. The transforming growth factor beta inhibitor Smad7 determines the phenotype of CD4<sup>+</sup> T cells. We hypothesized that Smad7 in intestinal CD4<sup>+</sup> T cells controls initiation of opticospinal encephalomyelitis (OSE), a murine model of multiple sclerosis (MS), depending on the presence of gut microbiota. Smad7 was overexpressed or deleted in OSE CD4<sup>+</sup> T cells to determine the effect on clinical progression, T cell differentiation, and T cell migration from the intestine to the central nervous system (CNS). Smad7 overexpression worsened the clinical course of OSE and increased CNS inflammation and demyelination. It favored expansion of intestinal CD4<sup>+</sup> T cells toward an inflammatory phenotype and migration of intestinal CD4<sup>+</sup> T cells to the CNS. Intestinal biopsies from MS patients revealed decreased transforming growth factor beta signaling with a shift toward inflammatory T cell subtypes. Smad7 in intestinal T cells might represent a valuable therapeutic target for MS to achieve immunologic tolerance in the intestine and suppress CNS inflammation.</p>}},
  author       = {{Haupeltshofer, Steffen and Leichsenring, Teresa and Berg, Sarah and Pedreiturria, Xiomara and Joachim, Stephanie C. and Tischoff, Iris and Otte, Jan Michel and Bopp, Tobias and Fantini, Massimo C. and Esser, Charlotte and Willbold, Dieter and Gold, Ralf and Faissner, Simon and Kleiter, Ingo}},
  issn         = {{0027-8424}},
  keywords     = {{Gut–brain axis; Multiple sclerosis; Smad7; T helper cell; TGF-beta}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{51}},
  pages        = {{25860--25869}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Smad7 in intestinal CD4<sup>+</sup> T cells determines autoimmunity in a spontaneous model of multiple sclerosis}},
  url          = {{http://dx.doi.org/10.1073/pnas.1905955116}},
  doi          = {{10.1073/pnas.1905955116}},
  volume       = {{116}},
  year         = {{2019}},
}