Failure to suppress the expansion of the activated CD4 T cell population in interferon gamma-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis

Mice deficient in interferon (IFN)-gamma or IFN-gamma receptor develop prog ressive and fatal experimental autoimmune encephalomyelitis (EAE). We demon strate that CD4 T cells lacking IFN-gamma production were required to passi vely transfer EAE, indicating that they were disease-mediating cells in IFN -gamma knockout (KO) mice. IFN-gamma KO mice accumulated 10-16-fold more ac tivated CD4 T cells (CD4(+)CD44(hi)) than wild-type mice in thr central ner vous system during EAE. CD4(+) CD44(hi) T cells in the spleen and central n ervous system of IFN-gamma KO mice during EAE showed markedly increased in vivo proliferation and significantly decreased es vivo apoptosis compared w ith those of wild-type mice. IFN-gamma KO CD4(+)CD44(hi) T cells proliferat ed extensively to antigen restimulation in vitro and accumulated larger num bers of live CD4(+)CD44(hi) T cells. IFN-gamma completely suppressed prolif eration and significantly induced apoptosis of CD4(+)CD44(hi) T cells respo nding to antigen and hence inhibited accumulation of live, activated CU4 T cells. We thus present novel in vivo and in vitro evidence that IFN-gamma m ay limit the extent of EAE by suppressing expansion of activated CD4 T cell s.