T cell signaling—initiated by the T cell receptor (TCR) binding its ligand, peptide in complex with MHC (pMHC)—is fundamental to the normal function of the adaptive immune system. Abnormal signaling can lead to diseases, whether by too much signaling (e.g., autoimmunity, allograft rejection, and graft vs. host disease), or too little (e.g., cancer, or susceptibility to viral infection). To tightly control signaling, an array of “cosignaling” receptors and ligands—either coinhibitory or costimulatory—ultimately determine the outcome of TCR:pMHC ligation. As such, these cosignaling molecules are promising therapeutic targets. We aim to understand the structural basis of receptor:ligand specificity, oligomerization (having important implications on cosignaling mechanisms), and interactions with antibodies that have therapeutic potential. These studies should both provide insight into the basic mechanisms of T cell signaling, and guide the design of new therapies that manipulate T cell signaling.