Substrate rigidity regulates human T cell activation and proliferation (52.9)

Abstract

Abstract Adoptive immunotherapy using cultured T cells holds promise for the treatment of cancer and infectious disease. Culture platforms based upon hard materials, such as polystyrene plastic, form the basis of many culture systems. The mechanical properties of a culture substrate can influence cellular adhesion, proliferation, and differentiation. We explored the impact of substrate stiffness on ex vivo T cell activation and polyclonal expansion using substrates with variable rigidity manufactured from poly(dimethylsiloxane) (PDMS), a biocompatible silicone elastomer. We show that the IL-2 production and ex vivo proliferation of human CD4+ and CD8+ T cells are increased an average of 4-fold following stimulation on softer (Young’s Modulus [E] < 100 kPa) compared with stiffer (E >2 MPa) substrates. Mixed peripheral blood T cells cultured on the stiffer substrates also demonstrate a trend towards a greater proportion of CD62Lneg, effector-differentiated CD4+ and CD8+ T cells. Culture of naïve CD4+ T cells on softer substrates yields an average 3-fold greater proportion of IFN-γ producing TH1-like cells. These findings reveal that the rigidity of the substrate used to immobilize T cell stimulatory ligands is an important and previously unrecognized parameter for T cell culture systems used for adoptive immunotherapy. These results also have implications for studies of T cell activation and signal transduction that use immobilized TCR/CD3 and CD28 ligands.