Lack of IL-4 receptor expression on T helper cells reduces T helper 2 cell polyfunctionality and confers resistance in allergic bronchopulmonary mycosis

Thelper (Th)1 and Th2 cells play decisive roles in the regulation of resistance vs. susceptibility to pulmonary cryptococcosis. To study the function of interleukin (IL)-4 receptor (IL-4R) on Th cells in pulmonary cryptococcosis, we infected mice specifically lacking IL-4R alpha on CD4(+) T cells (Lck(Cre)IL-4R alpha(-/lox) mice) and IL-4R alpha(-/lox) controls. Lck(Cre) IL-4R alpha(-/lox) mice developed enhanced resistance accompanied by reduced pulmonary allergic inflammation and diminished production of the Th2 cytokines IL-4, IL-5, and IL-13 as compared with IL-4R alpha(-/lox) mice. Polyfunctional antigen-specific Th2 cells producing simultaneously two or three Th2 cytokines were reduced in infected Lck(Cre) IL-4R alpha(-/lox) mice, pointing to a critical role of polyfunctional Th2 cells for disease progression. Reduced Th2 polyfunctionality was associated with fewer pulmonary alternatively activated macrophages. This work is the first direct evidence for a critical contribution of the IL-4R on Th cells to Th2-dependent susceptibility during allergic bronchopulmonary mycosis. Moreover, the data demonstrate that the quality of the Th2 response has an impact on type 2 inflammation. The analysis of polyfunctional Th2 cells may be useful for monitoring the course of the disease.