Artificial Biosystem for Modulation of Interactions between Antigen‐Presenting Cells and T Cells

Abstract

T cell activation is triggered by signal molecules on the surface of antigen‐presenting cells (APC) and subsequent exertion of cellular forces. Deciphering the biomechanical and biochemical signals in this complex process is of interest and will contribute to an improvement in immunotherapy strategies. To address underlying questions, coculture and biomimetic models are established. Mature dendritic cells (mDC) are first treated with cytochalasin B (CytoB), a cytoskeletal disruption agent known to lower apparent cellular stiffness and reduction in T cell proliferation is observed. It is attempted to mimic mDC and T cell interactions using polyacrylamide (PA) gels with defined stiffness corresponding to mDC (0.2–25 kPa). Different ratios of anti‐CD3 (aCD3) and anti‐CD28 (aCD28) antibodies are immobilized onto PA gels. The results show T cell proliferation is triggered by both aCD3 and aCD28 in a stiffness‐dependent manner. Cells cultured on aCD3 immobilized on gels has significantly enhanced proliferation and IL‐2 secretion, compared to aCD28. Furthermore, ZAP70 phosphorylation is enhanced in stiffer substrate a in a aCD3‐dependent manner. The biosystem provides an approach to study the reduction of T cell proliferation observed on CytoB‐treated mDC. Overall, the biosystem allows distinguishing the impact of biophysical and biochemical signals of APC and T cell interactions in vitro.

Mouse T cell priming is enhanced by maturation-dependent stiffening of the dendritic cell cortex

“…Importantly, it appears that the TCR's ability to sense stiffness is closely related to its ability to transduce force-dependent signals during T cell-APC interaction. Indeed, there is evidence that signaling downstream of TCR engagement is increased on stiffer substrates (Alatoom et al, 2020;Judokusumo et al, 2012) and that the intracellular location of early tyrosine phosphorylation events corresponds to sites of maximum traction force (Bashour et al, 2014). We propose that stiffer substrates allow T cells to exert more force through TCR interactions, and consequently induce more effective signaling.…”

“…Our findings raise the possibility that changes in DC cortical stiffness, like other maturation-induced changes, enhance the ability of these cells to prime a T cell response. Previous studies have shown that T cells are sensitive to the stiffness of stimulatory surfaces ( Alatoom et al, 2020 ; Judokusumo et al, 2012 ; O'Connor et al, 2012 ), and that the TCR serves as the mechanosensor ( Judokusumo et al, 2012 ). However, the results are conflicting, and these studies were not performed within the physiological stiffness range that we have defined for DCs.…”

“…In other cell types, substrate stiffness has been shown to affect a variety of cell functions including differentiation, migration, growth, and survival ( Byfield et al, 2009 ; Discher et al, 2005 ; Engler et al, 2006 ; Lo et al, 2000 ; Oakes et al, 2009 ; Pelham and Wang, 1997 ; Solon et al, 2007 ; Trappmann et al, 2012 ). Stiffness sensing in T cells has not been well studied, though there is some evidence that substrate stiffness affects both initial priming and effector functions ( Alatoom et al, 2020 ; Basu et al, 2016 ; Judokusumo et al, 2012 ; O'Connor et al, 2012 ; Saitakis et al, 2017 ). Since the physiologically relevant substrate for T cell priming is the surface of the interacting APC, one might predict that changes in cortical stiffness of the APC will profoundly influence T cell priming.…”

Hydrogels for Engineering the Immune System

“…Nevertheless, the mechanism of how anti‐CD28 and stiffness jointly modulate T‐cell proliferation is still unclear and requires further research. [ 122 ]…”

“…Nevertheless, the mechanism of how anti-CD28 and stiffness jointly modulate T-cell proliferation is still unclear and requires further research. [122] Figure 5. Hydrogels strikingly ameliorated ICB therapeutic toxicity and reversed immunosuppressive TME.…”