Mechanotransduction in T Cell Development, Differentiation and Function

Abstract

Cells in the body are actively engaging with their environments that include both biochemical and biophysical aspects. The process by which cells convert mechanical stimuli from their environment to intracellular biochemical signals is known as mechanotransduction. Exemplifying the reliance on mechanotransduction for their development, differentiation and function are T cells, which are central to adaptive immune responses. T cell mechanoimmunology is an emerging field that studies how T cells sense, respond and adapt to the mechanical cues that they encounter throughout their life cycle. Here we review different stages of the T cell's life cycle where existing studies have shown important effects of mechanical force or matrix stiffness on a T cell as sensed through its surface molecules, including modulating receptor-ligand interactions, inducing protein conformational changes, triggering signal transduction, amplifying antigen discrimination and ensuring directed targeted cell killing. We suggest that including mechanical considerations in the immunological studies of T cells would inform a more holistic understanding of their development, differentiation and function.

Keywords: T cell antigen receptor; catch bond; force; lymphocytes; stiffness; thymocytes.

Figure 1

Mechanotransduction occurs throughout the life cycle of T lineage cells. Schematic depicting development of a T lineage cell and instances where receptors on the developing cell have been studied to be subject to forces. Lymphoid progenitor encounters Notch and commits to a T cell lineage in the thymus; at the DN3 stage of thymocyte development, the pre-T cell antigen receptor (TCR) may bind to pMHC under force; at the developmental stage from double positive (DP) to single-positive (SP) thymocytes, migration from cortex to medulla is controlled by force-modulated ligand dissociation of β₁ integrins; the αβTCR relies on force to discriminate between positive and negative selection ligands; the naïve CD8⁺ T cell is activated when TCR is triggered by pMHC under force; memory T cells survive the contraction phase in part through TCR signaling.

Figure 2

Forces induce differential outcomes at different T cell development stages. Schematic depicting four developmental stages of T cells and how receptors experience force. (A) Notch receptor undergoes force induced conformational changes to reveal cryptic sites for proteolytic cleavage by γ-secretase and a disintegrin and metalloprotease (ADAM) allowing for nuclear translocation of the Notch intracellular domain (NICD). (B) A hydrophobic patch created by Vβ and pTα allows for broad pMHC binding and is potentially force stabilized by the FG-loop of Cβ. (C) Similar to thymocyte selection, which relies on dynamic catch bonds to discriminate between positive and negative selection ligands, dynamic bonds can facilitate discrimination between the antigens that are stimulatory or non-stimulatory.

Figure 3

Deformation exerted by naïve T cells and cytotoxic lymphocytes. Schematics depicting how naïve and cytotoxic T cells deform their target substrates. (A) Cell spreading is most optimal when the Young’s modulus of the substrate is on the order of 10–100kPa. (B) Cytotoxic T lymphocytes (CTLs) spatially coordinate F-actin polymerization and lytic granule localization to mechanical hotspots where force can potentiate the release of granules.

Figure 4

T cell activation by Piezo. Illustration depicting how force exerted on Piezo can induce entry of calcium flux resulting in T cell activation.