Intravenous Gammaglobulin Inhibits Encephalitogenic Potential of Pathogenic T Cells and Interferes with their Trafficking to the Central Nervous System, Implicating Sphingosine-1 Phosphate Receptor 1–Mammalian Target of Rapamycin Axis

Abstract

Despite an increasing use of high-dose therapy of i.v. gammaglobulin (IVIg) in the treatment of various T cell– and Ab-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. Using an actively induced experimental autoimmune encephalomyelitis model, a T cell–mediated autoimmune condition, we demonstrate that IVIg inhibits the differentiation of naive CD4 T cells into encephalitogenic subsets (Th1 and Th17 cells) and concomitantly induces an expansion of Foxp3+ regulatory T cells. Further, IVIg renders effector T cells less pathogenic by decreasing the expression of encephalitogenic molecular players like GM-CSF and podoplanin. Intriguingly and contrary to the current arguments, the inhibitory FcγRIIB is dispensable for IVIg-mediated reciprocal modulation of effector and regulatory CD4 subsets. Additionally, F(ab′)2 fragments also retained this function of IVIg. IVIg or F(ab′)2 fragments decrease the sphingosine-1 phosphate receptor on CD4 cells, thus sequestering these cells in the draining lymph nodes and decreasing their infiltration into the CNS. Our study reveals a novel role of Igs in the modulation of polarization and trafficking of T lymphocytes, accounting for the observed beneficial effect in IVIg therapy.