Dysregulated activation of T cells leads to pathogenic immune response to self-antigens. Despite an increasing use of high dose therapy of intravenous gammaglobulin (IVIg) in the treatment of T-cell and autoantibody-mediated inflammatory and autoimmune diseases, comprehension of the mechanisms underlying its therapeutic benefit has remained a major challenge. Particularly, the effect of IVIg in T cell mediated autoimmune conditions remains unexplored. I have investigated the effect of high dose IVIg on T cell polarization using actively induced experimental autoimmune encephalomyelitis (EAE), a T cell-mediated autoimmune condition. IVIg inhibits the differentiation of naïve CD4 T cells into effector subsets (Th1 and Th17 cells) and concomitantly induces an expansion of Foxp3+ regulatory cells. IVIg decreases the tissue damaging potential of pathogenic T cells by down regulating GM-CSF and podoplanin. Additionally, IVIg circumvents the neuronal damage by inhibiting the infiltration of CD4 T lymphocytes to the central nervous system by restraining their egress from the DLN through S1P-S1P1-mTOR pathway. Intriguingly and contrary to the current arguments, the inhibitory FcγRIIB and sialylation of IgG are dispensable for IVIg-mediated reciprocal modulation of effector and regulatory CD4 subsets. Altogether, therapeutic benefit of IVIg in EAE involves shifting the balance from Th17/Th1 towards Treg, down-regulating encephalitogenic mediators and inhibition of T cell trafficking to the target organ.
