AUTHOR=Dishon Shira , Cohen Shmuel J. , Cohen Irun R. , Nussbaum Gabriel 

TITLE=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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 8 - 2017

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00615

DOI=10.3389/fimmu.2017.00615

ISSN=1664-3224

ABSTRACT=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 APCs, and by inhibiting T-cell responses to IL-18. We now report that inhibition of MyD88 in human APCs led to decreased IFN 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 IFN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.