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A Method For Production of Recombinant mCD1d Protein in Insect Cells.
Published on: December 10, 2007
Cardiolipin binds to CD1d and stimulates CD1d-restricted γδ T cells in the normal murine repertoire
Mélanie Dieudé1, Harald Striegl, Aaron J Tyznik
1Division of Rheumatology, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec H3G 1A4, Canada.
Insights
Cardiolipin, a lipid molecule, is presented by CD1d molecules to specific T cells. These T cells, found in healthy mice, respond to cardiolipin and may aid in immune surveillance during infection and injury.
Area of Science:
- Immunology
- Structural Biology
- Cell Biology
Background:
- Cardiolipin (CL) is a key phospholipid in bacterial membranes and is sequestered in mitochondria, acting as a potential danger signal.
- Phospholipids are recognized as ligands for CD1 molecules, and CD1d-restricted T cells can recognize phospholipids.
- The interaction between CD1d and CL in the context of T cell recognition is not fully understood.
Purpose of the Study:
- To investigate if CD1d binds and presents cardiolipin (CL).
- To determine if T cells in the normal immune repertoire respond to CL in a CD1d-restricted manner.
- To elucidate the structural basis of CD1d-CL interaction and its functional consequences.
Main Methods:
- Determined the crystal structure of murine CD1d bound to CL.
- Performed lipid loading experiments to analyze CL binding to CD1d.
- Assessed the in vitro proliferation and cytokine secretion (IFN-γ, RANTES) of splenic and hepatic γδ T cells in response to CL.
- Investigated in vivo activation of hepatic γδ T cells by CD1d-bearing dendritic cells pulsed with CL.
Main Results:
- The crystal structure revealed that CL binds to murine CD1d with two alkyl chains inserted into the binding groove and two exposed to the solvent.
- Splenic and hepatic γδ T cells from healthy mice proliferated in response to both mammalian and bacterial CL in a dose-dependent and CD1d-restricted manner.
- Activated T cells rapidly secreted IFN-γ and RANTES.
- In vivo experiments showed activation of hepatic γδ T cells by CL-pulsed dendritic cells, but not by phosphatidylcholine-pulsed cells.
Conclusions:
- CD1d can bind and present CL to a subset of CL-responsive γδ T cells present in healthy mice.
- These CL-responsive γδ T cells may play a role in host defense against bacterial lipids and potentially self-CL.
- CL-responsive γδ T cells are proposed to be involved in immune surveillance during infection and tissue injury.
Abstract:
Cardiolipin (CL), a major phospholipid in bacterial cell walls, is sequestered from the immune system in mammalian mitochondria and is, therefore, a potential danger signal. Based on growing evidence that phospholipids constitute natural ligands for CD1 and that CD1d-restricted T cells recognize phospholipids, we hypothesized that CD1d binds and presents CL and that T cells in the normal immune repertoire respond to CL in a CD1d-restricted manner. We determined the murine CD1d-CL crystal structure at 2.3 Å resolution and established through additional lipid loading experiments that CL, a tetra-acylated phospholipid, binds to murine CD1d with two alkyl chains buried inside the CD1d binding groove and the remaining two exposed into the solvent. We furthermore demonstrate the functional stimulatory activity of CL, showing that splenic and hepatic γδ T cells from healthy mice proliferate in vitro in response to mammalian or bacterial CL in a dose-dependent and CD1d-restricted manner, rapidly secreting the cytokines IFN-γ and RANTES. Finally, we show that hepatic γδ T cells are activated in vivo by CD1d-bearing dendritic cells that have been pulsed with CL, but not phosphatidylcholine. Together, these findings demonstrate that CD1d is able to bind and present CL to a subset of CL-responsive γδ T cells that exist in the spleen and liver of healthy mice and suggest that these cells could play a role in host responses to bacterial lipids and, potentially, self-CL. We propose that CL-responsive γδ T cells play a role in immune surveillance during infection and tissue injury.
