Abstract
αβ T lymphocytes sense perturbations in host cellular body components induced by infectious pathogens, oncogenic transformation, or chemical or physical damage. Millions to billions of these lymphocytes are generated through T-lineage development in the thymus, each endowed with a clonally restricted surface T-cell receptor (TCR). An individual TCR has the capacity to recognize a distinct "foreign" peptide among the myriad of antigens that the mammalian host must be capable of detecting. TCRs explicitly distinguish foreign from self-peptides bound to major histocompatibility complex (MHC) molecules. This is a daunting challenge, given that the MHC-linked peptidome consists of thousands of distinct peptides with a relevant nonself target antigen often embedded at low number, among orders of magnitude higher frequency self-peptides. In this Masters of Immunology article, I review how TCR structure and attendant mechanobiology involving nonlinear responses affect sensitivity as well as specificity to meet this requirement. Assessment of human tumor-cell display using state-of-the-art mass spectrometry physical detection methods that quantify epitope copy number can help to provide information about requisite T-cell functional avidity affording protection and/or therapeutic immunity. Future rational CD8 cytotoxic T-cell-based vaccines may follow, targeting virally induced cancers, other nonviral immunogenic tumors, and potentially even nonimmunogenic tumors whose peptide display can be purposely altered by MHC-binding drugs to stimulate immune attack.