Abstract
The T cell function of a proliferation inducing ligand (APRIL or TNFSF13) remains unclear. By comparing APRIL-/- mice with wild type (WT) mice, we have investigated the roles of APRIL in Th1, Th2 and Th17 responses. With regard to APRIL in Th1 responses, cultured APRIL-/- CD4+ T cells showed increased IFN-gamma production under non-polarizing, but not under Th1 polarizing, conditions. No difference in antigen-specific IgG2a levels existed between APRIL-/- and WT mice immunized with ovalbumin (OVA) and complete Freund's adjuvant (CFA) which induces Th1 polarization. Our data indicate that APRIL represses Th1 responses only under non-polarizing conditions. As for APRIL in Th2 responses, cultured APRIL-/- CD4+ T cells exhibited enhanced Th2 cytokine production under non-polarizing conditions, and augmented IL-13 production under Th2 polarizing conditions. Upon immunization with OVA and aluminum potassium sulfate (alum) which induces Th2 polarization, APRIL-/- mice responded with an increased antigen-specific IgG1 response. In the OVA-induced allergic lung inflammation model which is mediated by Th2 responses, APRIL-/- mice had significantly aggravated allergic lung inflammation. Accordingly, a decoy receptor-Ig fusion protein, TACI-Ig, treatment to block APRIL in WT mice enhanced allergic lung inflammation. In agreement with the role of APRIL in CD4+ T cells, the transfer of APRIL sufficient, OVA-specific, TCR transgenic CD4+ T (OT-II) cells to APRIL-/- mice restored the suppressive effect of APRIL on allergic lung inflammation. Mechanistically, the expression of c-maf, the IL-4 gene transcription factor, was markedly enhanced in APRIL-/- CD4+ T cells under non-polarizing and Th2 polarizing conditions. Our data suggest that APRIL inhibits Th2 responses and allergic lung inflammation by suppressing IL-4 production in CD4+ T cells via diminished c-maf expression, and by suppressing IL-13 production in CD4+ T cells via an IL-4 independent, IL-13 specific pathway. Regarding APRIL in Th17 responses, the incidence of Th17-mediated collagen-induced arthritis (CIA) in APRIL-/- mice was reduced, in parallel with diminished levels of antigen-specific IgG2a autoantibody and IL-17 production. Our data indicate that APRIL promotes IL-17 production, and that APRIL-triggered signals contribute to arthritis. Our data clearly show that APRIL is important in T cell immunity, inhibitory in Th2 responses and costimulatory in Th17 responses.