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Complete but curtailed T-cell response to very low-affinity antigen


After an infection, T cells that carry the CD8 marker are activated and undergo a characteristic kinetic sequence of rapid expansion, subsequent contraction and formation of memory cells1,2,3. The pool of naive T-cell clones is diverse and contains cells bearing T-cell antigen receptors (TCRs) that differ in their affinity for the same antigen4,5. How these differences in affinity affect the function and the response kinetics of individual T-cell clones was previously unknown. Here we show that during the in vivo response to microbial infection, even very weak TCR–ligand interactions are sufficient to activate naive T cells, induce rapid initial proliferation and generate effector and memory cells. The strength of the TCR–ligand interaction critically affects when expansion stops, when the cells exit lymphoid organs and when contraction begins; that is, strongly stimulated T cells contract and exit lymphoid organs later than weakly stimulated cells. Our data challenge the prevailing view that strong TCR ligation is a prerequisite for CD8+ T-cell activation. Instead, very weak interactions are sufficient for activation, but strong TCR ligation is required to sustain T-cell expansion. We propose that in response to microbial challenge, T-cell clones with a broad range of avidities for foreign ligands are initially recruited, and that the pool of T cells subsequently matures in affinity owing to the more prolonged expansion of high-affinity T-cell clones.

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Figure 1: Unequal propagation of OT-1 and endogenous CD8 + T cells.
Figure 2: The strength of TCR ligation dictates the timing of T-cell contraction.
Figure 3: The strength of TCR ligation determines migration kinetics.
Figure 4: Low-potency TCR ligands induce functional memory cells.

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We thank A. Gallegos for advice in making the recombinant Listeria, and X.-C. Pan, B. Dere, B. Paul and K. Rider for technical support. Financial support was received from the National Institutes of Health and the Howard Hughes Medical Institute (M.J.B.), and from the Juvenile Diabetes Research Foundation and the German Research Foundation (D.Z.).

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Correspondence to Michael J. Bevan.

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Zehn, D., Lee, S. & Bevan, M. Complete but curtailed T-cell response to very low-affinity antigen. Nature 458, 211–214 (2009).

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