Complete but curtailed T-cell response to very low-affinity antigen - PubMed (original) (raw)

. 2009 Mar 12;458(7235):211-4.

doi: 10.1038/nature07657. Epub 2009 Jan 28.

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

Dietmar Zehn et al. Nature. 2009.

Abstract

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 cells. 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 antigen. 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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Figures

Fig. 1

Fig. 1. Unequal propagation of OT-1 and endogenous CD8+ T cells

C57/BL6 mice were grafted with 3×103 naïve CD45.1 OT-1 cells and infected with Listeria monocyogenes expressing Ova. On days 4 and 7 p.i., total splenocytes were harvested and briefly re-stimulated with Ova peptide in vitro. A, Representative CD8+ gated flow plots of splenocytes stimulated with or without 10 µM peptide are shown. Frequencies refer to total CD8+ cells. B, The ratios of the numbers of OT-1 and endogenous IFNγ+ T cells found in individual mice are graphically presented. C and D, Peptide dose-response curves normalized to the level of maximum numbers of IFNγ producing OT-1 and endogenous Kb/Ova-specific T cells are depicted (N=4 day 4, N=3 day 7), bars show standard error.

Fig. 2

Fig. 2. The strength of TCR ligation dictates the timing of T cell contraction

Mice were grafted with 104 unlabeled (in A, C, D, E) or 2×105 CFSE labeled naïve OT-1 cells (B) and infected with wildtype (wt) or recombinant Listeria monocytogenes expressing Ova protein containing native SIINFEKL (N4) or the indicated altered peptide ligands (APL), listed in order of decreasing potency (Supp. Fig. 2). A, The frequency of OT-1 among CD8+ cells in the blood at day 6 p.i., the insert shows Lm-V4 and wt Listeria on a magnified scale; B, CFSE dilution profiles of splenic OT-1 cells at day 3.25 p.i.; C, Numbers of splenic OT-1 cells at the indicated time points (N=4 per group and timepoint); D, Frequency of OT-1 among CD8+ blood cells at the indicated time points (N=5), bars show standard error; and E, Surface CCR7 and CD25 levels on splenic OT-1 at day 4 p.i.

Fig. 3

Fig. 3. The strength of TCR ligation determines migration kinetics

104 (A,B) and 3×103 naïve OT-1 cells (C) were transferred into C57/BL6 mice, which were subsequently infected with Lm-N4ova or Lm-APLova strains. A, Representative flow plots of CD8+ gated white blood cells showing the frequency of OT-1 cells at 4 days p.i. B, shows data for all APL (N=5). C, Splenic sections taken at day 4 p.i. show the distribution of OT-1 cells stimulated by N4 or Q4. OT-1 cells are green and B cells are blue. The border of PALS and red pulp is marked and arrows indicate OT-1 cells within the red pulp.

Fig. 4

Fig. 4. Low potency TCR ligands induce functional memory cells

Mice were grafted with congenic naïve OT-1 cells and infected with Lm-wt, Lm-N4ova or Lm-APLova strains. A, Representative flow plots of the frequencies of memory OT-1 among blood CD8+ T cells at day 138 p.i. B, the contraction and memory kinetics for all mice and all APL (N=5) until day 138 p.i. C, Mice were rechallenged on day 138 p.i. with VSV-N4ova and the frequencies of OT-1 among blood CD8+ T cells were determined 4 days later. The upper panels show representative flow plots and the lower depicts the data for all mice (N=5), with triangles indicating the frequency before and squares the frequency after the recall. Bars show standard error.

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