T helper (h)1/Th2 and Leishmania: paradox rather than paradigm

Studies on Leishmania major have been largely responsible for the characterisation of the Th1/Th2 paradigm of healing/non-healing associated with intracellular infection. IFN-gamma and IL-4 were identified respectively as the counter-regulatory Th1 and Th2 cytokines promoting resistance and susceptibility to infection. While resistance against infection remains largely associated with an IL-12 induced type-1 response studies using in particular gene-deficient mice have questioned the paramount role of IL-4 in the non-healing disease and implicated several alternative candidates. Indeed IL-4 has been shown to have no exacerbatory role in murine visceral leishmaniasis while its contribution to the progression of cutaneous disease has been clearly shown to be influenced not only by the parasite species but also the mouse strain used. Furthermore, it is now well established that not only can Th2 responses be induced independently of IL-4 but IL-4 under certain circumstances can prime for IL-12 production and a type-1 response. Clearly a reappraisal of our current understanding of the role of IL-4 and the Th2 response in the immunobiology of leishmaniasis is required and this review seeks to address this issue.