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Failure to Induce Neonatal Tolerance in Mice That Lack Both IL-4 and IL-13 but Not in Those That Lack IL-4 Alone¹

Yoshihiko Inoue^*, Bogumila T. Konieczny^*, Maylene E. Wagener^*, Andrew N. J. McKenzie and Fadi G. Lakkis^2,*

^* Renal Division, Department of Medicine, Emory University and Veterans Affairs Medical Center, Atlanta, GA 30033; and Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom

Current evidence suggests that neonatal tolerance to a foreign Ag is the consequence of IL-4-mediated Th2 immunity rather than the thymic deletion of Ag-specific T cells. Here, we addressed the role of IL-4 in neonatal tolerance by testing whether tolerance to a minor histocompatibility Ag can be induced in newborn mice that lack IL-4 (IL-4^-/-). We found that IL-4 does not play a dominant role in the induction of neonatal tolerance as newborn female IL-4^-/- mice could be readily tolerized to the H-Y male Ag. In contrast, mice that lack both IL-4 and IL-13 (IL-4^-/-/IL-13^-/-) were resistant to the induction of neonatal tolerance, and their splenocytes produced exaggerated amounts of IFN- on rechallenge with the same Ag encountered during the neonatal period. These findings argue against the view that IL-4 alone is critical for the induction of neonatal tolerance and suggest that the combined actions of both IL-4 and IL-13 are essential for this process.

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