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Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, and
Cellular Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892
In the present study, we examined the relationships among
quantitative aspects of TCR engagement as measured by receptor
down-modulation, functional responses, and biochemical signaling events
using both mouse and human T cell clones. For T cells from both
species, ligands that are more potent in inducing functional responses
promote TCR down-modulation more efficiently than weaker ligands. At
low ligand density, the number of down-modulated TCR exceeds the number
of available ligands by as much as 80–100:1 in the optimal human case,
confirming the previous description of serial ligand engagement of TCR
(Valitutti, et al. 1995. Nature 375:148–151). A previously
unappreciated relationship involving TCR down-modulation, the pattern
of proximal TCR signaling, and the extent of serial engagement was
revealed by analyzing different ligands for the same TCR. Functionally,
more potent ligands induce a higher proportion of fully tyrosine
phosphorylated 
-chains and a greater amount of phosphorylated ZAP-70
than less potent ligands, and the number of TCR down-modulated per
available ligand is higher with ligands showing this full agonist-like
pattern. The large number of receptors showing partial
phosphorylation following exposure to weak ligands indicates that the
true extent of TCR engagement and signaling, and thus the amount of
sequential engagement, is underestimated by measurement of TCR
down-modulation alone, which depends on full receptor activation. These
data provide new insight into T cell activation by revealing a clear
relationship among intrinsic ligand quality, signal amplification by
serial engagement, functional T cell responses, and observable TCR
clearance from the cell surface.
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A. L. Meyer, C. Trollmo, F. Crawford, P. Marrack, A. C. Steere, B. T. Huber, J. Kappler, and D. A. Hafler Direct enumeration of Borrelia-reactive CD4 T cells ex vivo by using MHC class II tetramers PNAS, October 10, 2000; 97(21): 11433 - 11438. [Abstract] [Full Text] [PDF]
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