T Cell Receptors Adapt by Spacing Out

Abstract

The detection of antigenic major histocompatibility complex (MHC)-peptide complexes by T lymphocytes has been likened to vision (1). In both cases, there is sensitivity to activation of single receptors. As with vision, the dynamic range of the stimuli can cover several orders of magnitude. The eye must be able to adapt to working in a starlit night or in noon sunshine and T cells must be able to respond to one MHC-peptide complex or thousands without undergoing activation-induced death. In this issue, Perica et al. (2) identify a mechanism by which T cells can transiently reduce their sensitivity to MHC-peptide complexes a few days after exposure to a “blinding” stimulus—effectively by spacing out receptors on the cell surface. The organization of T cell receptors (TCRs) and coreceptors on the cell surface has been an area of increasing interest. Evidence for preclustering of TCRs has come from biochemical analysis and direct microscopic observations (3). The molecular ruler of Forster resonance energy transfer has also been utilized to study the relationship between TCRs and coreceptors (4). Fahmy et al. (5) determined earlier that naive T cells are unable to bind soluble dimeric MHC-peptide complexes, whereas activated T cells bind these MHC-peptide dimers with high avidity. These results correlate with the relative ability of naive and activated T cells to detect low doses of antigen on the surface of antigen-presenting cells and provides a much more tractable assay. Variations in clustering could account for these results on theoretical grounds (6), but experiments to test this were lacking and the field has been in some disarray due to confusion about whether antigen exposure increased or decreased subsequent polyvalent ligand binding. In their report, Perica et al. (2) compare co-receptor-dependent MHC-peptide dimer binding to T cells a few days after activation by high and low doses of MHC-peptide complexes. Using high and low doses of antigens at relatively short times was key to capturing conditions in which activated cells display strong or weak ligand dimer binding. They find that cells activated at low doses bind the dimer avidly as they previously reported, whereas those activated with high doses cannot bind the dimers despite having the same surface density of TCRs and CD8. Analysis of TCR clustering and TCR-CD8 Forster resonance energy transfer demonstrated that TCRs on cells activated by high doses of MHC-peptide complex for short times are more spaced out, both from each other and from CD8, compared to TCRs on cells activated with low dose MHC-peptide complexes for short times. Later the high-dose-activated T cells recover ligand dimer binding and TCRs and CD8 come back together on the surface. These findings identify a new, to our knowledge, mechanism by which T cells control their sensitivity to antigens. These apparently new findings provide a framework for understanding disparate observations in the field and establishes an assay to pursue a molecular basis for how TCR clustering and TCR-CD8 spacing are controlled to adjust T cell sensitivity.