Critical contribution of OX40 ligand to T helper cell type 2 differentiation in experimental leishmaniasis

Infection of inbred mouse strains with Leishmania major is a well character ized model for analysis of T helper (Th)1 and Th2 cell development in vivo. In this study, to address the role of costimulatory molecules CD27, CD30, 4-1BB, and OX40, which belong to the tumor necrosis factor receptor superfa mily, in the development of Th1 and Th2 cells ill vivo, we administered mon oclonal antibody (mAb) against their ligands, CD70, CD30 Ligand (L), 4-1BBL , and OX40L, to mice infected with L. major. Whereas anti-CD70, anti-CD30L, and anti-4-1BBL mAb exhibited no effect in either susceptible BALB/c or re sistant C57BL/6 mice, the administration of anti-OX40L mAb abrogated progre ssive disease in BALB/c mice. Flow cytometric analysis indicated that OX40 was expressed on CD4(+) T cells and OX40L was expressed on CD11c(+) dendrit ic cells in the popliteal lymph nodes of L. major-infected BALB/c mice. In vitro stimulation of these CD4(+) T cells showed that anti-OX40L mAb treatm ent resulted in substantially reduced production of Th2 cytokines. Moreover , this change in cytokine levels was associated with reduced levels of anti -L. major immunoglobulin (Ig)G1 and serum ISE. These results indicate that anti-OX40L mAb abrogated progressive leishmaniasis in BALB/c mice by suppre ssing the development of Th2 responses, substantiating a critical role of O X40-OX40L interaction in Th2 development in vivo.