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The surprising diversity of lipid antigens for CD1-restricted T cells
1Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
CD1 proteins have been conserved throughout mammalian evolution and function to present lipid antigens to T cells. Crystal structures of CD1-lipid complexes show that CD1 antigen-binding grooves are composed of four pockets and two antigen entry portals. This structural information now provides a detailed understanding of how CD1-binding grooves capture a surprisingly diverse array of lipid ligands. CD1-expressing APCs are able to acquire lipid antigens from their own pool of lipids and from exogenous sources, including microbial pathogens, bystander cells, or even the systemic circulation. CD1 proteins bind to certain antigens using high stringency loading reactions within endosomes that involve low pH, glycosidases, and lipid transfer proteins. Other antigens can directly load onto CD1 proteins using low stringency mechanisms that are independent of cellular factors. New evidence from in vivo systems shows that CD1-restricted T cells influence outcomes in infectious, autoimmune, and allergic diseases. These studies lead to a broader view of the natural function of alphabeta T cells, which involves recognition of both cellular proteins and lipids.
Insights
CD1 proteins present diverse lipid antigens to T cells, influencing immunity and disease. Understanding CD1 structure and function reveals T cell recognition of both proteins and lipids.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- CD1 proteins are conserved in mammals, presenting lipid antigens to T cells.
- Structural data reveals CD1 antigen-binding grooves accommodate diverse lipid ligands.
- CD1-expressing antigen-presenting cells (APCs) acquire lipids from various internal and external sources.
Purpose of the Study:
- To detail the structural basis for CD1's diverse lipid antigen binding.
- To elucidate the mechanisms of CD1-lipid antigen loading.
- To explore the in vivo roles of CD1-restricted T cells in disease.
Main Methods:
- Analysis of crystal structures of CD1-lipid complexes.
- Investigation of CD1 antigen loading pathways (high and low stringency).
- In vivo studies of CD1-restricted T cell functions.
Main Results:
- CD1 antigen-binding grooves possess specific structural features (pockets, portals) for lipid capture.
- CD1 utilizes both high-stringency (endosomal, factor-dependent) and low-stringency (direct) loading mechanisms.
- CD1-restricted T cells impact infectious, autoimmune, and allergic diseases.
Conclusions:
- Structural insights explain CD1's broad lipid antigen repertoire.
- CD1-lipid antigen loading is a complex, regulated process.
- CD1-restricted T cells play significant roles in various disease contexts, expanding the known functions of T cells.
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