Defects of mitogen-activated protein kinase in ICOS signaling pathway lead to CD4+ and CD8+ T-cell dysfunction in patients with active SLE

In this study, hypoproliferation and defects of effectors and cytokines in CD4+ and CD8+ T-cells via ICOS costimulation were found in active SLE patients, relative to normal individuals and RA patient controls. Exogenous IL-2 can partially reverse those defects. In addition, low level of ERK phosphorylation in ICOS-mediated signaling pathway was discovered in lupus CD4+ and CD8+ T-cells. When blocked with ERK-specific chemical inhibitor PD98059, cell proliferation and IL-2 production via ICOS costimulation from both CD4+ and CD8+ T-cells will be severely inhibited. These findings confirmed the dysfunction of both CD4+ and CD8+ T-cells after ICOS costimulation in lupus patients and most importantly pointed out that impairment of ERK activation might be one of the critical factors involved in ICOS-mediated IL-2 and T-cell hypoproliferation in active SLE.