Butte Lab

Immunological Synapse

The interaction of T cells and APCs occurs within the immunological synapse (IS), a specialized area of contact and communication between the cells. Costimulatory receptors, the T cell receptor (TCR), and adhesion molecules selectively mobilize to this area and regulate responses. Clustering in the synapse is a dynamic process: IS formation depends on ligand binding, proximal signaling by kinases, calcium flux, cytoskeletal reorganization, and costimulation. CD28 is not only reorganized as the IS forms, but its signaling plays a vital role in the organization of the synapse itself by mediating the recruitment of lipid rafts and Lck to the IS. CD28 signaling within the synapse is required for sustained T cell activation and IL-2 production. CTLA-4 recruitment to the IS is proportional to TCR signal strength, which supports the notion that diminished inhibition by CTLA-4 at the IS can perpetuate the activity of weakly-active T cell clones and favor the activation of a broad repertoire of T cells. Together, these studies show that regulation of T cell activation is tightly controlled by the timing and activity of costimulatory receptors and ligands in the synapse.

One outstanding puzzle is what controls the recruitment of costimulatory molecules into the synapse. This question is clearly important: The balancing of B7-1 interactions with CD28, CTLA-4, and PD-L1 receptors on the T cell can skew the T cell response toward either activation or inhibition. The temporal expression of these molecules gives only a partial answer: TCR activation mobilizes CD28 into the synapse within minutes, whereas CTLA‑4 is trafficked to the IS over hours to days. These results substantiate their known functions: CD28 signaling is required for accentuation and perpetuation of the TCR signal, and CTLA‑4 can later sequester ligands from CD28 and signal to terminate TCR activation.

PD-L1 is abundantly present on the naïve T cell and is even upregulated upon activation. Moreover, PD-L1 has a higher affinity for B7-1 than does CD28. Why does PD-L1 not “win” over CD28 in the competition for B7-1? We will be testing a number of hypothesis to address this question.


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