B7-H4Ig inhibits mouse and human T-cell function and treats EAE via IL-10/Treg-dependent mechanisms

Joseph R. Podojil, Linda N. Liu, Shannon A. Marshall, Ming Yi Chiang, Gwen E. Goings, Lieping Chen, Solomon Langermann, Stephen D. Miller

Research output: Contribution to journalArticle

Abstract

We evaluated the therapeutic efficacy and mechanisms of action of both mouse and human B7-H4 Immunoglobulin fusion proteins (mB7-H4Ig; hB7-H4Ig) in treating EAE. The present data show that mB7-H4Ig both directly and indirectly (via increasing Treg function) inhibited CD4+ T-cell proliferation and differentiation in both Th1- and Th17-cell promoting conditions while inducing production of IL-10. B7-H4Ig treatment effectively ameliorated progression of both relapsing (R-EAE) and chronic EAE correlating with decreased numbers of activated CD4+ T-cells within the CNS and spleen, and a concurrent increase in number and function of Tregs. The functional requirement for Treg activation in treating EAE was demonstrated by a loss of therapeutic efficacy of hB7-H4Ig in R-EAE following inactivation of Treg function either by anti-CD25 treatment or blockade of IL-10. Significant to the eventual translation of this treatment into clinical practice, hB7-H4Ig similarly inhibited the invitro differentiation of naïve human CD4+ T-cells in both Th1- and Th17-promoting conditions, while promoting the production of IL-10. B7-H4Ig thus regulates pro-inflammatory T-cell responses by a unique dual mechanism of action and demonstrates significant promise as a therapeutic for autoimmune diseases, including MS.

Original languageEnglish (US)
Pages (from-to)71-81
Number of pages11
JournalJournal of Autoimmunity
Volume44
DOIs
StatePublished - Aug 2013
Externally publishedYes

Keywords

  • Autoimmunity
  • B7-H4
  • CD4 T-cell
  • Costimulatory/co-inhibitory molecule
  • EAE
  • Regulatory T-cells

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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    Podojil, J. R., Liu, L. N., Marshall, S. A., Chiang, M. Y., Goings, G. E., Chen, L., Langermann, S., & Miller, S. D. (2013). B7-H4Ig inhibits mouse and human T-cell function and treats EAE via IL-10/Treg-dependent mechanisms. Journal of Autoimmunity, 44, 71-81. https://doi.org/10.1016/j.jaut.2013.04.001