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Functional convergence of CD28 costimulation and TCR signaling is critical to T-cell activation and adaptive immunity. These receptors form complex microscale patterns within the immune synapse, although the impact of this spatial organization on cell signaling remains unclear. We investigate this cross talk using micropatterned surfaces that present ligands to these membrane proteins in order to control the organization of signaling molecules within the cell-substrate interface. While primary human CD4(+) T cells were activated by features containing ligands to both CD3 and CD28, this functional convergence was curtailed on surfaces in which engagement of these two systems was separated by micrometer-scale distances. Moreover, phosphorylated Lck was concentrated to regions of CD3 engagement and exhibited a low diffusion rate, suggesting that costimulation is controlled by a balance between the transport of active Lck to CD28 and its deactivation. In support of this model, disruption of the actin cytoskeleton increased Lck mobility and allowed functional T-cell costimulation by spatially separated CD3 and CD28. In primary mouse CD4(+) T cells, a complementary system, reducing the membrane mobility increased the sensitivity to CD3-CD28 separation. These results demonstrate a subcellular reaction-diffusion system that allows cells to sense the microscale organization of the extracellular environment.

Original publication

DOI

10.1128/mcb.00842-13

Type

Journal article

Journal

Molecular and cellular biology

Publication Date

03/2014

Volume

34

Pages

955 - 964

Addresses

Department of Biomedical Engineering, Columbia University, New York, New York, USA.

Keywords

CD4-Positive T-Lymphocytes, Cell Line, Animals, Humans, Mice, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Membrane Proteins, Antigens, CD28, Antigens, CD3, Signal Transduction