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 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Antia, R., Ganusov, V. V. & Ahmed, R. The role of models in understanding CD8+ T-cell memory. Nature Rev. Immunol. 5, 101–111 (2005)
Blattman, J. N. et al. Estimating the precursor frequency of naive antigen-specific CD8 T cells. J. Exp. Med. 195, 657–664 (2002)
Williams, M. A. & Bevan, M. J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007)
Turner, S. J., Doherty, P. C., McCluskey, J. & Rossjohn, J. Structural determinants of T-cell receptor bias in immunity. Nature Rev. Immunol. 6, 883–894 (2006)
Wilson, D. B. et al. Specificity and degeneracy of T cells. Mol. Immunol. 40, 1047–1055 (2004)
Badovinac, V. P., Haring, J. S. & Harty, J. T. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8(+) T cell response to infection. Immunity 26, 827–841 (2007)
Henrickson, S. E. et al. T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nature Immunol. 9, 282–291 (2008)
Joshi, N. S. et al. Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281–295 (2007)
Sarkar, S. et al. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J. Exp. Med. 205, 625–640 (2008)
Stemberger, C. et al. A single naive CD8+ T cell precursor can develop into diverse effector and memory subsets. Immunity 27, 985–997 (2007)
Kaech, S. M. & Wherry, E. J. Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity 27, 393–405 (2007)
Gronski, M. A. et al. TCR affinity and negative regulation limit autoimmunity. Nature Med. 10, 1234–1239 (2004)
Khanna, K. M., McNamara, J. T. & Lefrancois, L. In situ imaging of the endogenous CD8 T cell response to infection. Science 318, 116–120 (2007)
Pamer, E. G. Immune responses to Listeria monocytogenes. Nature Rev. Immunol. 4, 812–823 (2004)
Hamilton, S. E., Wolkers, M. C., Schoenberger, S. P. & Jameson, S. C. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nature Immunol. 7, 475–481 (2006)
Slifka, M. K. & Whitton, J. L. Functional avidity maturation of CD8+ T cells without selection of higher affinity TCR. Nature Immunol. 2, 711–717 (2001)
Xiao, Z., Mescher, M. F. & Jameson, S. C. Detuning CD8 T cells: down-regulation of CD8 expression, tetramer binding, and response during CTL activation. J. Exp. Med. 204, 2667–2677 (2007)
Phillips, R. E. et al. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354, 453–459 (1991)
Voeten, J. T. et al. Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes. J. Virol. 74, 6800–6807 (2000)
Selin, L. K. et al. Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunity. Immunol. Rev. 211, 164–181 (2006)
Alam, S. M. et al. T-cell-receptor affinity and thymocyte positive selection. Nature 381, 616–620 (1996)
Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006)
Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003)
Pope, C. et al. Organ-specific regulation of the CD8 T cell response to Listeria monocytogenes infection. J. Immunol. 166, 3402–3409 (2001)
Lauer, P., Chow, M. Y., Loessner, M. J., Portnoy, D. A. & Calendar, R. Construction, characterization, and use of two Listeria monocytogenes site-specific phage integration vectors. J. Bacteriol. 184, 4177–4186 (2002)
Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001)
Acknowledgements
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.).
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Supplementary Information
This file contains Supplementary Figures 1-10 with Legends and Supplementary Methods (PDF 1244 kb)
Rights and permissions
About this article
Cite this article
Zehn, D., Lee, S. & Bevan, M. Complete but curtailed T-cell response to very low-affinity antigen. Nature 458, 211–214 (2009). https://doi.org/10.1038/nature07657
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature07657
This article is cited by
-
T cell independent antibody responses with class switch and memory using peptides anchored on liposomes
npj Vaccines (2024)
-
The 4-1BBζ costimulatory domain in chimeric antigen receptors enhances CD8+ T-cell functionality following T-cell receptor stimulation
Cancer Cell International (2023)
-
Membrane-anchored DNA nanojunctions enable closer antigen-presenting cell–T-cell contact in elevated T-cell receptor triggering
Nature Nanotechnology (2023)
-
c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity
Nature Communications (2023)
-
A breast cancer classification and immune landscape analysis based on cancer stem-cell-related risk panel
npj Precision Oncology (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.