Mouse genetic background is a major determinant of isotype-related differences for antibody-mediated protective efficacy against Cryptococcus neoformans

The protective efficacy of mAbs to Cryptococcus neoformans glucuronoxylomannan depends on Ab isotype. Previous studies in A/JCr and C57BL/6J mice showed relative protective efficacy of IgG1, IgG2a ≫ IgG3. However, we now report that in C57BL/6J × 129/Sv mice, IgG3 is protective while IgG1 is not protective, with neither isotype being protective in 129/Sv mice. IgG1, IgG2a, and IgG3 had different effects on IFN-γ expression in infected C57BL/6J x 129/Sv mice. IgG1-treated C57BL/6J × 129/Sv mice had significantly more pulmonary eosinophilia than IgG2a- and IgG3-treated C57BL/6J × 129/Sv mice. C. neoformans infection and Ab administration had different effects on FcγRI, FcγRII, and FcγRIII expression in C57BL/6J, 129/Sv, and C57BL/6J × 129/Sv mice. Our results indicate that the relative efficacy of Ab isotype function against C. neoformans is a function of the genetic background of the host and that IgG3-mediated protection in C57BL/6J × 129/Sv mice was associated with lower levels of IFN-γ and fewer pulmonary eosinophils. The dependence of isotype efficacy on host genetics underscores a previously unsuspected complex relationship between the cellular and humoral arms of the adaptive immune response.