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NKT cell activation by Leishmania mexicana LPG: Description of a novel pathway
Jaime Zamora-Chimal1, Edith A Fernández-Figueroa1, Adriana Ruiz-Remigio1
1Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Hospital General de México, Dr. Balmis 148, Ciudad de Mexico C.P. 06726, Mexico.
Abstract:
NKT cells have been associated with protection against Leishmania donovani, yet their role in infections with Leishmania mexicana has not been addressed, nor has the activation pathway been defined after stimulation with Leishmania mexicana lipophosphoglycan (LPG). We analyzed the activation of NKT cells and their cytokine production in response to Leishmania mexicana LPG. Additionally we compared NKT-cell numbers and cytokine profile in lymph nodes of skin lesions induced by Leishmania mexicana in BALB/c and C57BL/6 mice. We show that LPG activates NKT cells primarily through the indirect pathway, initiating with TLR2 stimulation of dendritic cells (DC), thereby enhancing TLR2, MHC II, and CD86 expressions and IL-12p70 production. This leads to IFN-γ production by NKT cells. C57BL/6 mice showed enhanced DC activation, which correlated with augmented IFN-γ production by NKT cells. Additionally, infected C57BL/6 mice showed elevated percentages of NKT cells with higher IFN-γ and IL-4 production in lymph nodes. We conclude that the response of NKT cells towards Leishmania mexicana LPG initiates with the indirect activation, after binding of LPG to TLR2 in DC. This indirect activation pathway enables NKT cells to produce IFN-γ during the innate phase of Leishmania infection, the magnitude of which differs between mouse strains.
Insights
Natural killer T (NKT) cells are activated indirectly by Leishmania mexicana lipophosphoglycan (LPG) via Toll-like receptor 2 on dendritic cells, leading to IFN-γ production during infection.
Area of Science:
- Immunology
- Parasitology
- Cellular Biology
Background:
- Natural killer T (NKT) cells are implicated in Leishmania donovani protection.
- The role of NKT cells in Leishmania mexicana infections and their activation pathways remain unclear.
- Leishmania mexicana lipophosphoglycan (LPG) is a key parasite component.
Purpose of the Study:
- To investigate NKT cell activation and cytokine production in response to Leishmania mexicana LPG.
- To define the activation pathway of NKT cells stimulated by Leishmania mexicana LPG.
- To compare NKT cell responses in different mouse strains (BALB/c and C57BL/6) during Leishmania mexicana infection.
Main Methods:
- Analysis of NKT cell activation and cytokine profiles (IFN-γ, IL-4, IL-12p70) in vitro and in vivo.
- Stimulation of dendritic cells (DCs) with Leishmania mexicana LPG.
- Assessment of DC surface marker expression (TLR2, MHC II, CD86).
- Comparison of NKT cell populations and cytokine production in lymph nodes of infected mice.
Main Results:
- Leishmania mexicana LPG activates NKT cells indirectly, primarily through TLR2 stimulation of DCs.
- LPG-stimulated DCs exhibit enhanced TLR2, MHC II, and CD86 expression and produce IL-12p70.
- Activated DCs induce IFN-γ production by NKT cells.
- C57BL/6 mice display more robust DC activation and higher NKT cell-derived IFN-γ production compared to BALB/c mice.
- Infected C57BL/6 mice show increased percentages of NKT cells with elevated IFN-γ and IL-4 levels in lymph nodes.
Conclusions:
- The response of NKT cells to Leishmania mexicana LPG is initiated via an indirect pathway involving TLR2 on DCs.
- This indirect activation facilitates NKT cell IFN-γ production during the innate phase of Leishmania infection.
- The magnitude of the NKT cell response to Leishmania mexicana differs between mouse strains, highlighting genetic influences on immune outcomes.
