αβ TCR-mediated recognition: relevance to tumor-antigen discovery and cancer immunotherapy

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.

Fig. 1. Processing and presentation of HLA-bound self- and foreign-peptides

A) Peptides are generated through proteolysis in the proteosome, transported to the endoplasmic reticulum by transporters associated with antigen processing (TAP), associated with HLA molecules therein and then exported and cell surface displayed. B) Artistic rendition of 50,000 to 100,000 peptide-MHC complex (pMHC) molecules on a cell surface (blue/purple) with a single tumor antigen (yellow) among the MHC-bound peptidome, emphasizing the daunting challenge of TCR-based recognition. This figure was rendered by Steve Moskowitz of Advanced Medical Graphics, Boston, MA.

Fig. 2. TCR complex interaction with peptide-MHC complex (pMHC)

A) TCR components (ectodomains, stalk connecting peptides [CP; depicted as red, blue, chartreuse, and turquoise lines], transmembrane [TM] segments and cytoplasmic tails) are labeled and shown in distinct colors. An enlarged view is shown in the box. Note that the single acid residue in each CD3 subunit is omitted here for clarity. The pMHC on the APC and the interacting CD8αβ co-receptor are not colored. In each panel, the Cβ FG loop is depicted by an asterisk (*). B) Lateral view of TCR receptor components in ribbon form (PDB:IFND, 1XM and 1JBJ) oriented above the T-cell membrane (grey). Adducted sugars are depicted in beige in space-filling (CPK) representation. CD3ζζ is absent since it lacks ecotodomains. C) Force on TCR-pMHC interaction initiates signaling (pMHC, orange; Cβ FG loop, magenta; and TCR complex, other colors). This figure was rendered by Steve Moskowitz of Advanced Medical Graphics, Boston, MA. See accompanying supplemental movies 1 and 2.