Journal
IMMUNOLOGICAL REVIEWS
Volume 229, Issue -, Pages 356-386Publisher
WILEY
DOI: 10.1111/j.1600-065X.2009.00778.x
Keywords
T-cell costimulation; structure; immunoglobulin superfamily; TNF; TNFR superfamily
Categories
Funding
- National Institute of Health [RO1AI007289, U54 GM074945]
- Immunooncology & Immunology Training Program [5T32CA009173]
- Cancer Center Support Grant [P3OCAO13330]
- Albert Einstein Macromolecular Therapeutics Development Facility
- NATIONAL CANCER INSTITUTE [T32CA009173] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI007289] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U54GM074945] Funding Source: NIH RePORTER
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Costimulatory receptors and ligands trigger the signaling pathways that are responsible for modulating the strength, course, and duration of an immune response. High-resolution structures have provided invaluable mechanistic insights by defining the chemical and physical features underlying costimulatory receptor:ligand specificity, affinity, oligomeric state, and valency. Furthermore, these structures revealed general architectural features that are important for the integration of these interactions and their associated signaling pathways into overall cellular physiology. Recent technological advances in structural biology promise unprecedented opportunities for furthering our understanding of the structural features and mechanisms that govern costimulation. In this review, we highlight unique insights that have been revealed by structures of costimulatory molecules from the immunoglobulin and tumor necrosis factor superfamilies and describe a vision for future structural and mechanistic analysis of costimulation. This vision includes simple strategies for the selection of candidate molecules for structure determination and highlights the critical role of structure in the design of mutant costimulatory molecules for the generation of in vivo structure-function correlations in a mammalian model system. This integrated 'atoms-to-animals' paradigm provides a comprehensive approach for defining atomic and molecular mechanisms.
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