Dendritic Cell Differentiation State and Their Interaction with NKT Cells Determine Th1/Th2 Differentiation in the Murine Model ofLeishmania majorInfection

Abstract

Recent reports demonstrated that dendritic cells (DC) sense inflammatory and microbial signals differently, redefining their classical subdivision into an immature endocytic and a mature Ag-presenting differentiation stage. Although both signals induce DC maturation by up-regulating MHC class II and costimulatory molecules, only TLR signals such as LPS are able to trigger proinflammatory cytokine secretion by DCs, including Th1-polarizing IL-12. Here, we explored the murine Leishmania major infection model to examine the CD4+ T cell response induced by differentially matured DCs. When partially matured TNF-DCs were injected into BALB/c mice before infection, the mice failed to control L. major infection and developed a Th2 response which was dependent on IL-4Rα signaling. In contrast, injections of fully matured LPS+CD40-DCs induced a Th1 response controlling the infection. Pulsing DCs with a lysate of L. major did not affect DC maturation with TNF-α or LPS+anti-CD40. When the expression of different Notch ligands on DCs was analyzed, we found increased expression of Th2-promoting Jagged2 in TNF-DCs, whereas LPS+CD40-DCs up-regulated the Th1-inducing Delta4 and Jagged1 molecules. The Th2 polarization induced by TNF-DCs required interaction with CD1d-restricted NKT cells. However, NKT cell activation by L. major lysate-pulsed DCs was not affected by blockade of the endogenous glycolipid, suggesting exchange with exogenous parasite-derived CD1 glycolipid Ag. In sum, the differentiation stage of DCs as well as their interaction with NKT cells determines Th1/Th2 differentiation. These results have generic implications for the understanding of DC-driven Th cell responses and the development of improved DC vaccines against leishmaniasis.

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

“…However, the application of semi-mature DCs in Th2-cell associated asthma model neither ameliorated nor worsened the disease symptoms, similarly to the previous data obtained for the murine L. major Th2-cell infection model [34]. These data suggest that the Th2/Tr1 differentiation as induced by semimature DCs in Th2-cell models results in a balance between an intrinsic inflammation-limiting Tr1 response and the active asthma-promoting Th2-cell response.…”

“…The protective response as induced by three injections of TNF-conditioned DCs in the EAE setting was controlled by the simultaneous activation of CD1d-dependent NKT cells, generating a rapid type 2 cytokine environment [33]. However, DCs partially matured by TNF were not able to prevent footpad swelling of mice in the leishmaniasis model, further contributing to the hypothesis that a Th2-cell immune deviation mechanism is responsible for the tolerance induction in the EAE model [34]. Again, the differences among the similar Th2/Tr1-inducing DC maturation profiles by inflammation or pathogens remained poorly investigated.…”

Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization

“…Human macrophages constitutively express Notch-1, Notch-2, Jag1, and Dll1 (40). Human and mice macrophages upregulated Notch-1 (46,53) and also Jag1 and Dll4 upon TLR4 ligation (35,42,46,(54)(55)(56). LPSinduced upregulation of Notch-1 and Jag1 seems to be dependent on p38 MAPK and NF-kB (46), and Dll4 increase depended on MyD88 (28).…”

Loss of PKCλ/ι impairs Th2 establishment and allergic airway inflammation in vivo

“…In dendritic cells, for example, Notch ligands, as well as the receptor tyrosine kinase, c-Kit, and its ligand, SCF, signal T lymphocytes to polarize to the Th1 or Th2 lineages, depending on the type of APC-stimulating trigger (12)(13)(14)(15).…”