The Enigmatic Nature of the TCR-pMHC Interaction: Implications for CAR-T and TCR-T Engineering

Abstract

The interaction of the T-cell receptor (TCR) with a peptide in the major histocompatibility complex (pMHC) plays a central role in the adaptive immunity of higher chordates. Due to the high specificity and sensitivity of this process, the immune system quickly recognizes and efficiently responds to the appearance of foreign and altered self-antigens. This is important for ensuring anti-infectious and antitumor immunity, in addition to maintaining self-tolerance. The most common parameter used for assessing the specificity of TCR-pMHC interaction is affinity. This thermodynamic characteristic is widely used not only in various theoretical aspects, but also in practice, for example, in the engineering of various T-cell products with a chimeric (CAR-T) or artificial (TCR-engineered T-cell) antigen receptor. However, increasing data reveal the fact that, in addition to the thermodynamic component, the specificity of antigen recognition is based on the kinetics and mechanics of the process, having even greater influence on the selectivity of the process and T lymphocyte activation than affinity. Therefore, the kinetic and mechanical aspects of antigen recognition should be taken into account when designing artificial antigen receptors, especially those that recognize antigens in the MHC complex. This review describes the current understanding of the nature of the TCR-pMHC interaction, in addition to the thermodynamic, kinetic, and mechanical principles underlying the specificity and high sensitivity of this interaction.

Dichotomy in TCR V-domain dynamics binding the opposed inclined planes of pMHC-II and pMHC-I α-helices

“…Thus, the specified parallel forces could reflect a mechanism present from nearly the beginning of the adaptive immune system, which might include a role for tangential shearing forces between the T-cell and APC membranes [6, 13-17]. One could envision such forces orchestrating remarkable energy differences between target and ‘off-target’ TCR:pMHC complexes [35], in essence facilitating the TCR scanning thousands of pMHC until ‘finding’ the target ligand. The trajectory of each V-domain to the apex of each IP modeled here is suggested by the common direction, yet there is clonotypic magnitude of F τ ⍰ values (Table 1).…”

“…One could envision such forces orchestrating remarkable energy differences between target and 'off-target' TCR:pMHC complexes [35], in essence facilitating the TCR scanning thousands of pMHC until 'finding' the target ligand. The trajectory of each V-domain to the apex of each IP modeled here is suggested by the common direction, yet there is clonotypic magnitude of F τ values (Table 1).…”

Optical sensing and control of T cell signaling pathways

“…TCRs recognize the pMHC via the complementarity determining regions (CDRs) in the variable domains of the TCR αβ chains ( Rossjohn et al, 2015 ). The variable domains are highly diversified through random genetic recombination of variable (V) and joining (J) gene segments, and with the exclusive presence of diversity (D) gene in the β chains, making the TCRs to distinguish and recognize a wide repertoire of antigen peptides ( Huang et al, 2012 ; Szeto et al, 2020 ; Shevyrev et al, 2022 ). The binding structure of TCR-pMHC is further stabilized by co-receptors CD4 and CD8 of T cells, forming the ternary complex of TCR-pMHC-co-receptors ( Morch et al, 2020 ; Rushdi et al, 2022 ).…”

Immunological mechanisms of tolerance: Central, peripheral and the role of T and B cells

“…Although not typically associated with tolerance, T cell exhaustion represents an important mechanism of tolerance in specific immunological situations. Phenotypically, exhausted T Cells (Tex) have evidence of reduced functional and proliferative capacities and display elevated levels of inhibitory receptor expression, including that of Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Lymphocyte-activation gene 3 (LAG3), Cluster of differentiation 244 (CD244), Cluster of differentiation 160 (CD160), T Cell immunoreceptor with Ig and ITIM domains (TIGIT), Cluster of differentiation 38 (CD38), Cluster of differentiation 39 (CD39), and T cell immunoglobulin (Ig) domain and mucin domain-containing protein 3 (TIM3) [ 4 ]. These exhausted T cells are classically associated with chronic viral infection and cancer; both instances in which T cells experience prolonged antigen stimulation.…”