Inhibition of myeloid differentiation factor 88 reduces human and mouse T-cell interleukin-17 and IFNγ production and ameliorates experimental autoimmune encephalomyelitis induced in mice

Shira Dishon, Shmuel J. Cohen, Irun R. Cohen, Gabriel Nussbaum*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Myeloid differentiation factor 88 (MyD88) recruits signaling proteins to the intracellular domain of receptors belonging to the toll-like/interleukin-1 (IL-1) receptor superfamily. Mice lacking MyD88 are highly susceptible to infectious diseases, but tend to resist experimentally induced autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and manifest diminished allograft rejection. We reasoned that inhibition of MyD88 should influence the cytokine profile of responding T cells by blocking costimulatory molecule expression by antigen-presenting cells (APCs) and by inhibiting T-cell responses to IL-18. We now report that inhibition of MyD88 in human APCs led to decreased IFNγ and IL-17 production and a shift to IL-4 production by responding T cells in a mixed lymphocyte reaction. Direct inhibition of Myd88 in mouse and human T cells also reduced their production of IFNγ in response to IL-12/IL-18 stimulation. Finally, systemic MyD88 antagonism significantly reduced the clinical manifestations of EAE in mice. Thus, MyD88 appears to be a key factor in determining T cell phenotype and represents a potential target for therapeutic intervention.

Original languageAmerican English
Article number615
JournalFrontiers in Immunology
Volume8
Issue numberMAY
DOIs
StatePublished - 29 May 2017

Bibliographical note

Publisher Copyright:
© 2017 Dishon, Cohen, Cohen and Nussbaum.

Keywords

  • Experimental autoimmune encephalomyelitis
  • Mixed lymphocyte reaction
  • Multiple sclerosis
  • Myeloid differentiation factor 88
  • Th1/Th2

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