T helper1/T helper2 cells and resistance/susceptibility to Leishmania infection: is this paradigm still relevant?

Work in large part on Leishmania major in the 1980s identified two distinct apparently counter-regulatory CD4(+) T cell populations, T helper (h)1 and Th2, that controlled resistance/susceptibility to infection respectively. However, the generation of IL-4(-/-) mice in the 1990s questioned the paramount role of this Th2 archetypal cytokine in the non-healing response to Leishmania infection. The more recent characterization of CD4(+) T cell regulatory populations and further effector CD4(+) T helper populations, Th17, Th9, and T follicular (f)h cells as well as the acknowledged plasticity in T helper cell function has further added to the complexity of host pathogen interactions. These interactions are complicated by the multiplicity of cells that respond to CD4(+) T cell subset signatory cytokines, as well as the diversity of Leishmania species that are often subject to significantly different immuneregulatory controls. In this article we review current knowledge with regard to the role of CD4(+) T cells and their products during Leishmania infection. In particular we update on our studies using conditional IL-4R alpha gene-deficient mice that have allowed dissection of the cell interplay dictating the disease outcomes of the major Leishmania species infecting humans.