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BALB/c mice infected with P. chabaudi AS develop immunity to erythrocytic-stage infection with early Th1 responses followed by a switch towards Th2 responses later to mediate protection during chronic disease. In order to determine the importance of the Th2 cytokines, IL-4/IL-13, in inducing protective immunity, the course of P. chabaudi infection was monitored in IL-4Rα-deficient mice. Interestingly, an early delay in the onset of peak parasitaemia in IL-4Rα-/- compared with WT control BALB/c mice was evident. Consequently, we demonstrated that IL-4Rα deficiency resulted in mice becoming more susceptible to chronic P. chabaudi infection with increased recrudescence, mortality and an impaired Th2 immune response compared with WT control mice. Similar results in the overall disease and immunological profiles between IL-4Rα-/- and wild-type mice were obtained whether male or female mice or the AJ or AS strains of P. chabaudi were used to infect mice. Thus, the protective role of IL-4Rα signalling during chronic disease was not parasite strain-specific or host gender dependent. However, males were significantly more susceptible than female mice and consequently further studies involving cell-type IL-4Rα-/- mice, utilized female mice to identify functional targets of IL-4/IL-13 protection. Abrogated IL-4Rα expression on macrophages/neutrophils (LysMcreIL-4Rα-/lox) mice had minimal effect on the outcome of P. chabaudi AS chronic infection and was comparable to WT mice implicating no major role for alternatively activated macrophages during chronic infection. In contrast, CD4+ T-cell-specific IL-4Rα-/- (LckcreIL-4Rα-/lox) mice infected with P. chabaudi AS developed increased recrudescence, increased mortality and impairment of Th2 immunity during the chronic infection similar to that of the global IL-4Rα-/- mice. This highlights the importance of signalling via CD4+ T-cells signalling via IL-4Rα for protective immunity during chronic infection. Paradoxically, CD4+CD8+ T-cell-specific IL-4Rα-/- (iLckcre IL-4Rα-/lox) mice displayed a similar disease profile to WT control mice but manifested a delayed Th2 phenotype during the latter stage of the disease with enhanced splenomegaly in comparison to the WT and IL-4Rα-/- mice. Thus while protection during chronic infection with P. chabaudi AS appears dependent on CD4+ T-cells responsive to IL-4, CD8+ T cells responsive to IL-4 have a more complex and more difficult role to interpret.

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