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Three-dimensional segregation of supramolecular activation clusters in T cells

Abstract

Activation of T cells by antigen-presenting cells (APCs) depends on the complex integration of signals that are delivered by multiple antigen receptors. Most receptor-proximal activation events in T cells1,2 were identified using multivalent anti-receptor antibodies, eliminating the need to use the more complex APCs. As the physiological membrane-associated ligands on the APC and the activating antibodies probably trigger the same biochemical pathways, it is unknown why the antibodies, even at saturating concentrations, fail to trigger some of the physiological T-cell responses3. Here we study, at the level of the single cell, the responses of T cells to native ligands. We used a digital imaging system and analysed the three-dimensional distribution of receptors and intracellular proteins that cluster at the contacts between T cells and APCs during antigen-specific interactions3,4. Surprisingly, instead of showing uniform oligomerization, these proteins clustered into segregated three-dimensional domains within the cell contacts. The antigen-specific formation of these new, spatially segregated supramolecular activation clusters may generate appropriate physiological responses and may explain the high sensitivity of the T cells to antigen.

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Figure 1: The localization of talin and PKC-θ at the three-dimensionally reconstructed T-cell–APC contact site.
Figure 2: The 3D redistribution of LFA-1 in antigen-specific T-APC conjugates.
Figure 3: The 3D redistribution of TCR–CD3 in antigen-specific (ar) but not in antigen-nonspecific (sx) T-cell–APC conjugates.
Figure 4: Quantitative analysis of the fractional distribution of receptors for the T-cell–APC contact site.
Figure 5: The 3D redistribution of TCR–CD3 and class II MHC in antigen-specific T-cell–APC conjugates.
Figure 6: The p-SMAC and c-SMAC.
Figure 7: Agonist peptides and not altered peptides cause the formation of SMACs.
Figure 8: The rapid translocation of Fyn and Lck to c-SMACs.

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Acknowledgements

We thank C. A. Janeway Jr, J. Miller and P. Marrack for reagents, cell lines and transgenic mice; J. Kappler and P. Marrack for comments; and D. Littman and J. Schlessinger for advice and critical reading of this manuscript. These studies were supported in part by grants from the NIH.

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Monks, C., Freiberg, B., Kupfer, H. et al. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998). https://doi.org/10.1038/25764

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