Monophosphoryl lipid A directly regulates Th1 cytokine production in human CD4+ T-cells through Toll-like receptor 2 and 4.

BACKGROUND:The monophosphoryl lipid A (MPLA) is a detoxified LPS derivative and an emerging safe immune adjuvant in human vaccine development. The adjuvant MPLA promotes antigen-presenting cell (APC) function and preferentially induces a Th1 response following vaccination. However, the mechanism by which the MPLA detoxicates and exerts its adjuvants effect on T-cell, particualrly the Th1 response is unknown. AIMS:We assessed the direct effects of MPLA on murine and human CD4+ T-cell proliferation and the profile of cytokine production ex vivo. RESULTS:We report that CD4+ T-cells only express functional TLR2 and TLR4 when activated by TCR stimulation, in particularly in the presence of IFNα. The activated T cells thereafter can respond directly to MPLA. MPLA does not affect T-cell proliferation in human T cells, but can induce a balanced Th1 cytokine profile in CD4+ T-cells by reducing the production of Th1 cytokines and enhancing the production of the regulatory cytokine IL-10. The MPLA-mediated regulatory effect on activated CD4+ T-cells is TLR2 and TLR4 dependent and can be abolished by the lipid A blocker polymyxin B. CONCLUSION:These data provide evidence, at least in part, for the safe induction of an appropriate level of Th1 response by adjuvant MPLA in human vaccine development.