T cell avidity determines the level of CTL activation

To investigate the influence of avidity on T cell activation in vitro and in vivo, we analyzed T cells from St40 and St42 mice, which express the same transgenic TCR specificfor an E1a‐derived epitope of adenovirus type 5 with different expression levels and therefore different avidities. Splenocytes from both strains showed comparable cytolytic activities and requiredidentical peptide concentrations for efficient target cell lysis and up‐regulation of activation markers. However, the kinetics of CD25 up‐regulation were strikingly different: whereas the majorityof the high‐avidity St42 T cells up‐regulated the IL‐2Rα chain within a few hours, low‐avidity St40 T cells expressed only 50% of the CD25 of high‐avidity T cells after 2 days. In addition, low‐avidity T cells proliferated poorly and displayed impaired secretion of IL‐2 and IFN‐γ. Similar results were seen with high‐avidity St42 T cells stimulated with a partial agonistic peptide. Upon adoptive transfer and subsequent immunization with adenovirus, both high‐ and low‐avidity T cells expanded, but St40 T cells were undetectable 10 days after immunization. Our model system now allowsanalysis of whether T cells with identical specificities but different avidities influence each other during activation and homeostatic proliferation.

[1]  Clemens Utzny,et al.  Lytic versus stimulatory synapse in cytotoxic T lymphocyte/target cell interaction: Manifestation of a dual activation threshold , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  N. Auphan-Anezin,et al.  Distinct Thresholds for CD8 T Cell Activation Lead to Functional Heterogeneity: CD8 T Cell Priming Can Occur Independently of Cell Division1 , 2003, The Journal of Immunology.

[3]  Carsten J. Kirschning,et al.  The Endoplasmic Reticulum-resident Heat Shock Protein Gp96 Activates Dendritic Cells via the Toll-like Receptor 2/4 Pathway* , 2002, The Journal of Biological Chemistry.

[4]  P. Matzinger.  The Danger Model: A Renewed Sense of Self , 2002, Science.

[5]  Michael Loran Dustin,et al.  T Cell Receptor Signaling Precedes Immunological Synapse Formation , 2002, Science.

[6]  M. A. Alonso,et al.  The role of lipid rafts in signalling and membrane trafficking in T lymphocytes. , 2001, Journal of cell science.

[7]  C Benoist,et al.  How much TCR does a T cell need? , 2001, Immunity.

[8]  A. Schmitt‐Verhulst,et al.  Differential Survival of Transferred CD8 T Cells and Host Reconstitution Depending on TCR Avidity for Host-Expressed Alloantigen1 , 2001, The Journal of Immunology.

[9]  T. Fahmy,et al.  Increased TCR avidity after T cell activation: a mechanism for sensing low-density antigen. , 2001, Immunity.

[10]  D. Wiest,et al.  On the dynamics of TCR:CD3 complex cell surface expression and downmodulation. , 2000, Immunity.

[11]  C Caux,et al.  Immunobiology of dendritic cells. , 2000, Annual review of immunology.

[12]  R. Flavell,et al.  Differential requirements for NF-kappaB and AP-1 trans-activation in response to minimal TCR engagement by a partial agonist in naive CD8 T cells. , 1999, Journal of immunology.

[13]  T. Schumacher,et al.  CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy , 1999, Nature Medicine.

[14]  J. Tschopp,et al.  Peptide modification or blocking of CD8, resulting in weak TCR signaling, can activate CTL for Fas- but not perforin-dependent cytotoxicity or cytokine production. , 1998, Journal of immunology.

[15]  R. Germain,et al.  Relationships among TCR ligand potency, thresholds for effector function elicitation, and the quality of early signaling events in human T cells. , 1998, Journal of immunology.

[16]  P. Allen,et al.  Selective activation of the calcium signaling pathway by altered peptide ligands , 1996, The Journal of experimental medicine.

[17]  R. Offringa,et al.  Peptide vaccination can lead to enhanced tumor growth through specific T-cell tolerance induction. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[18]  H. Eisen,et al.  Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response. , 1996, Immunity.

[19]  M. Bevan,et al.  Selective activation of Fas/Fas ligand-mediated cytotoxicity by a self peptide , 1996, The Journal of experimental medicine.

[20]  T. Braciale,et al.  Partial activation of CD8+ T cells by a self-derived peptide , 1995, Nature.

[21]  A. Lanzavecchia,et al.  Serial triggering of many T-cell receptors by a few peptide–MHC complexes , 1995, Nature.

[22]  L. Samelson,et al.  Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists , 1995, Science.

[23]  Paul M. Allen,et al.  Partial T cell signaling: Altered phospho-ζ and lack of zap70 recruitment in APL-induced T cell anergy , 1994, Cell.

[24]  A. B. Lyons,et al.  Determination of lymphocyte division by flow cytometry. , 1994, Journal of immunological methods.