Mechanical control of antigen detection and discrimination by T and B cell receptors

Abstract

The adaptive immune response is orchestrated by just two cell types, T cells and B cells. Both cells possess the remarkable ability to recognize virtually any antigen through their respective antigen receptors-the T cell receptor (TCR) and B cell receptor (BCR). Despite extensive investigations into the biochemical signaling events triggered by antigen recognition in these cells, our ability to predict or control the outcome of T and B cell activation remains elusive. This challenge is compounded by the sensitivity of T and B cells to the biophysical properties of antigens and the cells presenting them-a phenomenon we are just beginning to understand. Recent insights underscore the central role of mechanical forces in this process, governing the conformation, signaling activity, and spatial organization of TCRs and BCRs within the cell membrane, ultimately eliciting distinct cellular responses. Traditionally, T cells and B cells have been studied independently, with researchers working in parallel to decipher the mechanisms of activation. While these investigations have unveiled many overlaps in how these cell types sense and respond to antigens, notable differences exist. To fully grasp their biology and harness it for therapeutic purposes, these distinctions must be considered. This review compares and contrasts the TCR and BCR, placing emphasis on the role of mechanical force in regulating the activity of both receptors to shape cellular and humoral adaptive immune responses.

Figure 1

BCR and TCR structures and antigens. (A) Schematic of the IgM-class BCR, showing the mIg and Igα/Igβ subunits. The mIg is composed of a heavy chain with four constant domains (C_μ1–4) and one variable domain (V_H), and a light chain with one constant domain (C_L) and one variable domain (V_L). The V_L and V_H domains comprise the antigen-binding unit. (B) Schematic showing the BCR binding a multivalent antigen (red) that is presented as part of an immune complex (antibody-antigen complex) presented by an antigen-presenting cell (APC) via an Fcγ receptor. Antigen binding triggers phosphorylation of Igα/Igβ ITAMs, leading to Syk recruitment. (C) Schematic of the αβ TCR. The TCR-α and TCR-β chains each contain a variable domain (Vα and Vβ) that together form the antigen-binding region, and a constant domain (Cα and Cβ). The CD3 complex contains the dimers CD3εγ, CD3εδ, and CD3ζζ. (D) Schematic of the TCR binding a peptide presented by MHC complex I (pMHCI), including engagement of the CD8 co-receptor with MHCI. Phosphorylation of CD3 ITAMs leads to the recruitment of ZAP-70. (B and D) The sensitivity of both B and T cells to antigens is enhanced by LFA-1-ICAM-1 engagement. T cell sensitivity is further enhanced by engagement of the CD28 co-receptor with its ligands CD80 and CD86. BCR and TCR activation is downregulated by the phosphatases CD45 (B and T cells) and CD148 (B cells). The figure was created in BioRender. To see this figure in color, go online.

Figure 2

Putative force-induced conformational changes to the BCR and TCR. (A) Forces that propagate from membrane-bound antigen through the IgM-BCR induce several BCR structural changes that potentiate intracellular signaling. Forces increase the distance between the N-terminus (antigen-binding site) and Cμ2 domain, unmask a clustering interface in the Cμ4 domain, and reposition Igα/Igβ cytoplasmic tails, making them more accessible to phosphorylation. Adapted from (58,59). (B) Forces propagate from the pMHCI-TCR binding site to CD3, exposing CD3 ITAMs to phosphorylation. Forces normal to the cell surface unfold the FG loop to extend the TCR structure and release CD3 cytoplasmic domains for phosphorylation, while forces tangential to the cell surface generate a torque that rotates the complex, resulting in the FG loop exerting a pushing force on CD3 that releases CD3 ITAMs. Adapted from (60). The figure was created in BioRender. To see this figure in color, go online.

Figure 3

Regulation of receptor-antigen binding by mechanical force. (A) Depiction of the association and dissociation of a soluble ligand to a membrane receptor and the solution on-rate ($k_{\text{on}}$) and off-rate ($k_{\text{off}}$). (B) A bond formed between a receptor and membrane-anchored ligand is exposed to a mechanical force, $f$. The bond then has a force-dependent off-rate, $k_{\text{off}}\left(f\right)$. (C) Within a microcluster, receptor-antigen bonds share the total mechanical load so that the force per bond, $f_{\text{bond}}$, is equal to the total applied force, $F_{\text{total}}$, divided by the total number of bonds, $n_{\text{bonds}}$. (D) Adhesion molecules shield receptor-antigen bonds from mechanical force. (E) The initiation of intracellular signaling leads to actin cytoskeleton remodeling and myosin II contractions that generate mechanical forces at the immune synapse. The figure was created in BioRender. To see this figure in color, go online.

Figure 4

Slip bonds versus catch-slip bonds. The lifetime of a slip bond (pink) decreases exponentially with increasing force. In contrast, the lifetime of a catch-slip bond (green) initially increases with force (catch phase) until an optimum value is reached, beyond which the bond dissociates more rapidly (slip phase). The figure was created in BioRender. To see this figure in color, go online.

Figure 5

Mechanical force underpins T cell and B cell effector functions. (A) Schematic of the cytotoxic T cell synapse. TCR-pMHC microclusters are transported toward the synapse center initially by retrograde actin flow and then by dynein-mediated movement along microtubules. Dynein also transports lytic granules to the synapse, where perforin and granzyme proteins are released. Myosin II-based forces exerted against the target cell increase target cell membrane tension, potentiating perforin pore formation, granzyme access to the target cell cytoplasm, and target cell killing. (B) Schematic of the B cell synapse. BCR-antigen microclusters are transported toward the synapse center by a combination of actin retrograde flow and dynein-microtubule transport. Myosin II contractile forces pull on BCR-antigen bonds, rupturing bonds with low-affinity antigens and promoting internalization of high-affinity antigens. Adapted from (53). The figure was created in BioRender. To see this figure in color, go online.