Role of CD4+ T cells and IFN-γ in autoantibody response in Zap70 mutant mice

An ENU-induced mutant mouse with a point mutation in the Zap70 gene was studied. This mutant Zap70 gene encodes a Zap70 protein with a single C to S amino acid substitution at residue 563. This Zap70 mutant mouse spontaneously produced autoantibody and was named “Sap” for “serum autoantibody positive.” The autoantibody response in Sap mice, as a function of age, was characterized by immunofluorescence, Western blotting, and immune complex deposition techniques. Sap mice at 5 wks of age made primarily anti-cytoplasmic autoantibodies. Sap mice over 8 wks of age, on the other hand, made predominantly anti-nuclear autoantibodies (ANA), most of which were of the IgG2a isotype. Sap mice also displayed glomeruli-associated immune complex deposition, most of which were of the IgM isotype. IgG2a ANA and immune complex deposition responses were lost in Sap-CD4-KO and Sap-IFN-γ-KO mice. Adoptive transfer of Sap CD4+ T cells restored the deficient ANA response in Sap-CD4-KO but not Sap-IFN-γ-KO hosts. Despite the loss of ANA, anti-cytoplasmic autoantibody response was still observed in Sap-IFN-γ-KO mice. These results clearly show the key roles played by CD4+ T cells and IFN-γ in the induction of the ANA response. They also implicate the importance of cells other than CD4+ T cells as the provider of IFN-γ in the induction of the ANA response.