Much of current  immunology research in is founded on enormous data sets, complex interactions, and computer modeling – tackling the microbiome or the origins of autoimmune disease, for example. Fundamental discoveries can seem few and far between amidst Big Data (data sets of size and complexity that computers are required for analysis, ‘-omics (proteomics, genomics, metabolomics), and epigenetic findings. But a recent breakthrough in microscopy may have settled an old immunological debate.

We recognize that immune memory– T and B cells rapidly activating to fight a known enemy- happens very quickly. The question of how, and how they’re so fast, has been sketchily theorized but not fully explained. Our best prior prevailing theory couldn’t account for the known speed of the reaction or what we thought we knew about T cell receptor distribution.

When immune cells interact, something called an ‘immune synapse’ forms. In the synapse are all the required receptors, co receptors and costimulatory molecules needed to trigger, prolong, and program an immune response. The prevailing theory has been that the required first step- T cell interaction with an antigen presenting cell (APC)- took time, as the TCR (the required receptor) was distributed in ‘nanoclusters’ in a few areas of the cell membrane.

In order to trigger a memory response, TCR and APC have to either a) start in the correct orientation to each other for interaction of the TCR-APC, or b) allow a significant amount of time for a TCR nanocluster  to migrate into the correct orientation. This theory requires random interaction followed by reorientation of the synapse to trigger an immune reaction. It was thought that clustering would allow precise, though not rapid, interactions between TCR and APC.

As modern microscopy has improved, irregular structures were seen on the T cell surface and interpreted as receptor nanoclusters. New evidence suggests, however, that our interpretation has been limited by our vision—literally!

Fundamental improvements in microscope resolution and data processing in the hands of Rossboth et al. make the old theory of nano-clustering improbable, if not impossible. Double counting of receptors created data suggesting more TCRs in a single area- a 3D structure populated by ‘real’ receptors and their double or triple-counted ‘ghost’ counterparts. Double-counting and the 3D representation of those counts accounted for the nanocluster architecture predicted and accepted as the prevailing theory.

The method of Rossboth et al resolves TCR placement to the single-receptor level, which prevents the mistake of double counting, and uses a statistical image analysis approach to eliminate the “noise” which contributed to the apparent existence of nanoclusters. In fact, the researchers demonstrate demonstrate that the “nanoclustering” effect is an artifact of the previous microscopy process.

TCR distribution
Nano-cluster model versus random distribution model of TCR arrangement

They posit a new theory: memory T cell receptors for cognate antigen are randomly distributed across the whole membrane area of a T cell membrane. This makes the TCR “lock” available to any passing antigen “key”—in all directions and at any time.

Further work, validation by other research groups and, eventually, a further evolution of direct imaging microscopy will determine if Rossboth et al. have solved this particular, fundamental aspect of T cell immunology. Understanding the first few steps in the triggering of an immune response opens a window into tailored immunity, better vaccines, and a deeper understanding of immunology.

Benedikt Rossboth et al., TCRs are randomly distributed on the plasma membrane of resting antigen-experienced T cells. Nature Immunology (2018). DOI: 10.1038/s41590-018-0162-7


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