Combination of and Heat-Induced Promastigotes Cures Drug-Resistant Infection: Critical Role of Interleukin-6-Producing Classical Dendritic Cells.

The major issues in available therapeutic modalities against leishmaniasis are cost, toxicity, and the emergence of drug resistance. The aim of this work was to develop a successful therapeutic adjuvant against drug-resistant infection by means of combining with heat-induced promastigotes (HIP). One-month postinfected BALB/c mice were administered subcutaneously with (10 cells) and HIP (100 μg) for 5 days. Spleens were harvested for flow cytometric and reverse transcriptase PCR analysis. The antileishmanial effect of the combination strategy was associated with induction of a disease-resolving Th1 and Th17 response with simultaneous downregulation of CD4 CD25 Foxp3 (nTreg) cells and CD4 CD25 Foxp3 (Tr1) cells in the spleen. The significant expansion of CD4 T (CD4 CD44 CD11a CD62L) cells was a further interesting outcome of this therapeutic strategy in the context of long-term protection of hosts against secondary infection. Toll-like receptor 2 (TLR2) was also found instrumental in this antiparasitic therapy. Induced interleukin-6 (IL-6) production from expanded CD11c CD8α (cDC1) and CD11c CD11b (cDC2) dendritic cells (DCs) but not from the CD11b Ly6c inflammatory monocytes (iMOs), was found critical in the protective expansion of Th17 as evidenced by an IL-6 neutralization assay. It also promoted the hematopoietic conversion toward DC progenitors (pre-DCs) from common dendritic cell progenitors (CDPs), the immediate precursors, in bone marrow. This novel combinational strategy demonstrated that expansion of Th17 by IL-6 released from CD11c classical DCs is crucial, together with the conventional Th1 response, to control drug-resistant infection.