Leishmania donovani mediated higher expression of CCL4 induces differential accumulation of CD4 + CD56 + NKT and CD8 + CD56 + NKT cells at infection site

摘要

Sterile cure from visceralizedLeishmania donovani(L. donovani) needs Th1 cell support along with the assistance from innate immune cells, NK cells and NKT cells. NKT cells play as a connecting link between innate and adaptive immune cell and support T helper cell function. Earlier, a categorical function of CD56 positive CD4+or CD8+NKT cells was reported in visceral leishmaniasis (VL). It was observed inin vitrothat CD4+CD56+NKT cells, but not CD8+CD56+NKT cells, were accumulated at theL. donovaniinfection site. Therefore,in vitroexperiments have been carried out to decipher the mechanism behind preferential accumulation of CD4+CD56+NKT cells at infection site. In this study, 1.89 fold higher expression of CCL4/MIP-1β was noticed in infected macrophages. The higher expression of CCL4 was correlated with preferential accumulation of CCR5+CD4+CD56+NKT cells and apoptosis of CD8+CD56+NKT cells atin vitroinfection site. The CD4+CD56+NKT cells were also observed expressing TGF-β dominantly. Interaction of CCL4 chemotaxis was interrupted by blocking, which led to drift back the TGF-β producing CD4+CD56+NKT cells and promoted CD8+CD56+NKT cells recruitment inin vitroinfection site. CCR5 blockade also reduced CD25 and FoxP3 positive CD4+CD56+NKT cells inin vitroinfection site. Therefore, it was concluded thatLeishmaniapromotes strategic expression of CCL4, which alternately attracts CCR5+cells, mostly expressing regulatory cytokines, at infection site. This reduces the CD8+CD56+NKT cells at infection site through Smad4 mediated TGF-β expression and activation of caspases. Data indicates thatL. donovaniinduces higher expression of CCL4 in host cell to attract CCR5+cells under its strategic plan to downregulate host immune response.