Molecular Mechanisms of T Cell Recognition
Our laboratory continues to work on fundamental processes by which T lymphocytes recognize foreign pathogens including viruses such as smallpox, vaccinia, HIV, and influenza A. We have analyzed the basic function and structure of the T cell receptor (TCR) components: TCRalphabeta heterodimer, CD3epsilongamma and CD3epsilondelta heterodimers, and CD3zetazeta homodimer. In addition, we have derived further detail about CD4 and CD8 coreceptors and their binding to the major histocompatibility complex (MHC) molecules of class II and class I, respectively.Recently, we have shown that agonist mAbs footprint to the membrane distal CD3epsilon lobe which they approach diagonally, adjacent to the lever-like Cbeta FG loop that facilitates antigen (pMHC)-triggered activation. In contrast, a non-agonist mAb binds to the cleft between CD3epsilon and CD3gamma in a perpendicular mode and is stimulatory only subsequent to an external tangential but not a normal force (~50 pN) applied via optical tweezers. Specific pMHC but not irrelevant pMHC activates a T cell upon application of a similar force. These findings suggest that the TCR is an anisotropic mechanosensor, converting mechanical energy into a biochemical signal upon specific pMHC ligation during immune surveillance. Activating anti-CD3 mAbs mimic this force via their intrinsic binding mode. A common TCR quaternary change rather than conformational alterations can better facilitate structural signal initiation, given the vast array of TCRs and their specific pMHC ligands.Using computational methods, we have also defined the rules concerning the nature of peptides that bind to individual human MHC molecules, including multiple allelic variants, and developed bioinformatic approaches to create computational vaccinology. Further, we have created servers for multiple vaccine development based on prediction of supertypic MHC ligands. We are currently pursuing new mass spectrometry approaches to identify peptides arrayed on individual types of antigen-presenting cells, and defining at a molecular level the extent of T cell recognition of individual immunodominant epitopes as well as non-immunodominant epitopes.In the next year, we expect to apply these tools and approaches for characterizing human immune recognition to the area of tumor immunology. In conjunction with the DFCI Cancer Vaccine Center, we will determine the utility of this approach for immunotherapy of cancers.