Deletion of MIF gene from live attenuated LdCen(−/−) parasites enhances protective CD4(+) T cell immunity

Vaccination with live attenuated Leishmania parasites such as centrin deleted Leishmania donovani (LdCen(−/−)) against visceral leishmaniasis has been reported extensively. The protection induced by LdCen(−/−) parasites was mediated by both CD4(+) and CD8(+) T cells. While the host immune mediators of protection are known, parasite determinants that affect the CD4(+) and CD8(+) T cell populations remain unknown. Parasite encoded inflammatory cytokine MIF has been shown to modulate the T cell differentiation characteristics by altering the inflammation induced apoptosis during contraction phase in experimental infections with Leishmania or Plasmodium. Neutralization of parasite encoded MIF either by antibodies or gene deletion conferred protection in Plasmodium and Leishmania studies. We investigated if the immunogenicity and protection induced by LdCen(−/−) parasites is affected by deleting MIF genes from this vaccine strain. Our results showed that LdCen(−/−)MIF(−/−) immunized group presented higher percentage of CD4(+) and CD8(+) central memory T cells, increased CD8(+) T cell proliferation after challenge compared to LdCen(−/−) immunization. LdCen(−/−)MIF(−/−) immunized group presented elevated production of IFN-γ(+) and TNF-α(+) CD4(+) T cells concomitant with a reduced parasite load in spleen and liver compared to LdCen(−/−)group following challenge with L. infantum. Our results demonstrate the role of parasite induced factors involved in protection and long-term immunity of vaccines against VL.