Lessons from Leishmania: a model for investigations of CD4+ subset differentiation

Infection of inbred mice with Leishmania major remains the best model of human infection with visceralizing Leishmania that cause kala-azar. Immunologic investigations have correlated the outcome of disease with expansion of different subsets of CD4+ cells, designated Th1 and Th2. Although the capacity of fixed effector Th1 and Th2 populations to mediate the diverse outcomes of disease through the release of soluble cytokines, particularly IFN-gamma and IL-4, has been demonstrated, the mechanisms by which these subsets become established during infection have not been delineated. This review focuses on known features of CD4+ differentiation using other experimental models, and proposes that genetic susceptibility to Leishmania can occur if the host has a Th2 precursor cell in the memory configuration prior to the time of exposure to organisms, perhaps in response to cross-reactive self-peptides. The hypothesis can explain a number of puzzling observations in both murine and human disease due to these organisms and makes several predictions amenable to experimental testing.