Atoms-to-Animals: Structural Genomics of Immunity

Immune Function Network (IFN), a consortium of immunologists, geneticists, computational biochemists, biophysicists and high throughput structural biologists, is committed to the coordinated structural, in vitro biochemical and in vivo functional analyses of the secreted molecules and ectodomains of cell surface molecules that control adaptive and innate immunity.

These molecules dictate the course, duration and strength of an immune response, and are validated targets for immune-based therapies to treat a wide range of autoimmune diseases, infectious diseases and cancers. The genes encoding these immune receptors, ligands and adhesive molecules often cluster into families that share common structural features crucial for function. The elaboration of the relationships between sequence, structure and immune function is the major goal of the IFN.

T cell activation results from signals received from two independent and distinct receptor-ligand recognition events. The first signaling event, which is responsible for the specificity of activation, results from interactions between the T cell receptor (TCR) on the surface of T cells and the peptide-MHC complex displayed on the surface of antigen presenting cells (APCs). Signal I alone is not sufficient for T cell activation and in the absence of a second distinct signal, results in either apoptotic death or prolonged unresponsiveness (anergy) of the responding T cell. The engagement of coinhibitory and costimulatory receptors and ligands in the central zone of the immunological synapse results in the recruitment and enrichment of cytoplasmic kinases, phosphatases and scaffolding proteins and it is the specific organizational properties of these localized signaling assemblies that propagate cascades for the enhancement and attenuation of T activity. Numerous additional costimulatory and coinhibitory molecules belonging to the Ig, TNF, TNFR, lectin and other superfamilies make critical contributions that regulate and coordinate the distinct cell populations required for a physiological immune response.

Soluble versions of these receptors and their cognate ligands themselves, as well as monoclonal antibodies (mAbs) targeted against these proteins, are major therapeutics as they can serve as agonists or antagonists of stimulatory and inhibitory pathways by blocking the normal interaction between cell surface molecules. In some cases, structural information has been crucial in the development and enhancement of these protein-based drugs, including our recent work on the PD-1 coinhibitory factor.