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Strong and Durable TCR Clustering at the T/Dendritic Cell Immune Synapse Is Not Required for NFAT Activation and IFN- Production in Human CD4⁺ T Cells^1,2

Institut National de la Santé et de la Recherche Médicale, Unité 520, Institut Curie, Paris, France

The exact function of TCR clustering and organized macromolecular patterns at the immune synapse between APCs and T lymphocytes is unclear. Using human immature or mature dendritic cells (DCs) and autologous CD4⁺ effector T cells, we demonstrate that, within a given conjugate, mature DCs induce strong and long-lasting TCR clustering and protein kinase C- translocation in a superantigen dose-dependent manner. Moreover, mature DCs promote CD43 exclusion in a dose-independent manner. In contrast, immature DCs are less potent at inducing these molecular rearrangements. Using these models to correlate T cell functions with the frequency, the intensity, and the duration of TCR clustering, we show, in Jurkat T cells, that weak and transient TCR clustering is sufficient to promote TCR down-modulation, protein kinase C- translocation at the synapse, and substantial NFAT transcriptional activation. Moreover, we show, in CD4⁺ T cell blasts, that strong TCR clustering is required for neither TCR down-modulation nor optimal IFN- production. Together, our results demonstrate that some CD4⁺ functional responses, such as cytokine production, are independent of central supramolecular activation cluster formation.

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