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Mouse Genetic Background Is a Major Determinant of Isotype-Related Differences for Antibody-Mediated Protective Efficacy against Cryptococcus neoformans^1,2

Johanna Rivera^* and Arturo Casadevall^3,*,

Departments of^* Microbiology and Immunology and Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY 10461

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 x 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- expression in infected C57BL/6J x 129/Sv mice. IgG1-treated C57BL/6J x 129/Sv mice had significantly more pulmonary eosinophilia than IgG2a- and IgG3-treated C57BL/6J x 129/Sv mice. C. neoformans infection and Ab administration had different effects on FcRI, FcRII, and FcRIII expression in C57BL/6J, 129/Sv, and C57BL/6J x 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 x 129/Sv mice was associated with lower levels of IFN- 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.

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