Hybrid cell vaccination resolves Leishmania donovani infection by eliciting strong CD8⁺CTL response with concomitant suppression of IL-10 but not IL-4 and IL-13

Department of Immunology, Indian Institute of Chemical Biology, Jadavpur, Calcutta, WB, India; Department of Dermatology and Allergy, Charite -Universitätsmedizin Berlin, Humboldt University, D-10098 Berlin, Germany; Central Instrumentation Division, Indian Institute of Chemical Biology, Jadavpur, Calcutta, WB, India

^* To whom correspondence should be addressed. Email: sroy{at}iicb.res.in.

	Abstract

There is an acute dearth of therapeutic intervention against visceral leishmaniasis that is required to restore an established defective cell-mediated immune response. Hence formulation of effective immunotherapy requires usage of dominant antigen (s) targeted to elicit specific anti-parasitic cellular immune response. We implemented hybrid cell vaccination therapy in Leishmania donovani infected BALB/c mice by electrofusing dominant Leishmania antigen (Kinetoplastid Membrane Protein-11)-transfected bone-marrow derived macrophages from BALB/c mice with allogeneic bone-marrow derived dendritic cells from C57BL/6. Hybrid cell vaccine (HCV) cleared splenic and hepatic parasite burden eliciting KMP-11 specific MHC class I restricted CD8⁺CTL responses. Moreover splenic lymphocytes of HCV-treated mice not only showed enhancement of IFN- but also marked elevated expression of the Th2 cytokines-IL-4 and IL-13 both at transcriptional and translational levels. On the other hand, IL-10 production from splenic T cells was markedly suppressed as a result of HCV therapy. CD8⁺ T cell depletion completely abrogated HCV-mediated immunity and anti-KMP-11 CTL response. Interestingly CD8⁺ T cell depletion-mediated completely abrogated HCV-induced immunity resulting in marked increase of IL-10 only but not of IL-4 and IL-13. This study reports the first implementation of HCV immunotherapy in an infectious disease model, establishing strong antigen-specific CTL generation as a correlate of HCV-mediated anti-leishmanial immunity that is reversed by in vivo CD8⁺T cell depletion of HCV-treated mice. The findings of our study might be extended to drug-unresponsive visceral leishmaniasis patients as well as against multiple infectious diseases with pathogen-specific immunodominant antigens.