The duration of antigenic stimulation determines the fate of naive and effector T cells.

It is known that T cells engage antigen-presenting cells (APCs) in a stable interaction that results in sustained TCR signaling. We show here that the duration of this process is critical in determining whether T cells will be activated or deleted. Whereas naive T cells require approximately 20 hr of sustained signaling to be committed to proliferation, effector T cells become committed after only 1 hr but die following activation if antigenic stimulation is prolonged. Costimulation by anti-CD28 facilitates T cell activation by decreasing the time of commitment and by protecting T cells from death. These findings explain in quantitative terms the essential requirement for professional APCs in T cell priming and show that the duration of antigenic stimulation is the major factor determining the fate of naive and effector T cells.

[1]  D. Cantrell,et al.  The interleukin-2 T-cell system: a new cell growth model. , 1984, Science.

[2]  Timothy A. Springer,et al.  Adhesion receptors of the immune system , 1990, Nature.

[3]  M. Lenardo.  lnterleukin-2 programs mouse αβ T lymphocytes for apoptosis , 1991, Nature.

[4]  Y. Chien,et al.  Early biochemical signals arise from low affinity TCR-ligand reactions at the cell-cell interface , 1996, The Journal of experimental medicine.

[5]  G. Crabtree,et al.  Promoter region of interleukin-2 gene undergoes chromatin structure changes and confers inducibility on chloramphenicol acetyltransferase gene during activation of T cells , 1986, Molecular and cellular biology.

[6]  C. Thompson,et al.  CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. , 1995, Immunity.

[7]  D. Alexander,et al.  CD3 antigen‐mediated calcium signals and protein kinase C activation are higher in CD45R0+ than in CD45RA+ human T lymphocyte subsets , 1993, European journal of immunology.

[8]  R. Zinkernagel,et al.  Immunological Memory , 2006 .

[9]  B. Seed,et al.  αLβ2 Integrin/LFA-1 Binding to ICAM-1 Induced by Cytohesin-1, a Cytoplasmic Regulatory Molecule , 1996, Cell.

[10]  David Gray,et al.  Immunological Memory and Protective Immunity: Understanding Their Relation , 1996, Science.

[11]  A. Weiss,et al.  Ligand-receptor interactions required for commitment to the activation of the interleukin 2 gene. , 1987, Journal of immunology.

[12]  L. Hood,et al.  Cotransfer of the Ed alpha and Ad beta genes into L cells results in the surface expression of a functional mixed-isotype Ia molecule. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[13]  P. Corthésy,et al.  Mouse interleukin-2 receptor alpha gene expression. Delimitation of cis-acting regulatory elements in transgenic mice and by mapping of DNase-I hypersensitive sites. , 1995, The Journal of biological chemistry.

[14]  A. Rolink,et al.  Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor , 1994, The Journal of experimental medicine.

[15]  R. Steinman,et al.  The dendritic cell system and its role in immunogenicity. , 1991, Annual review of immunology.

[16]  Rolf M. Zinkernagel,et al.  Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells , 1993, Nature.

[17]  L. Terry,et al.  Limiting dilution analysis of proliferative responses in human lymphocyte populations defined by the monoclonal antibody UCHL1: implications for differential CD45 expression in T cell memory formation , 1988, European journal of immunology.

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

[19]  G. Crabtree.  Contingent genetic regulatory events in T lymphocyte activation. , 1989, Science.

[20]  K. Horgan,et al.  The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. , 1990, Journal of immunology.

[21]  C. Janeway,et al.  Molecular associations on the T cell surface correlate with immunological memory , 1990, European journal of immunology.

[22]  Antonio Lanzavecchia,et al.  T Cell Activation Determined by T Cell Receptor Number and Tunable Thresholds , 1996, Science.

[23]  Emil R. Unanue,et al.  Quantitation of antigen-presenting cell MHC class II/peptide complexes necessary for T-cell stimulation , 1990, Nature.

[24]  H. Teh,et al.  Differential activation of phospholipase C-gamma 1 and mitogen-activated protein kinase in naive and antigen-primed CD4 T cells by the peptide/MHC ligand. , 1996, Journal of immunology.

[25]  M. Croft,et al.  Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. , 1994, Journal of immunology.

[26]  M. Jackson,et al.  Requirements for Peptide-induced T Cell Receptor Downregulation on Naive CD8+ T Cells , 1997, The Journal of experimental medicine.

[27]  J. Allison,et al.  Activation and differentiation requirements of primary T cells in vitro. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[28]  H. Grey,et al.  The minimal number of class II MHC-antigen complexes needed for T cell activation. , 1990, Science.

[29]  J. Bluestone,et al.  CD28/B7 system of T cell costimulation. , 1996, Annual review of immunology.

[30]  W. Paul,et al.  Ia antigen-bearing B cell tumor lines can present protein antigen and alloantigen in a major histocompatibility complex-restricted fashion to antigen-reactive T cells , 1982, The Journal of experimental medicine.

[31]  Martine Tomkowiak,et al.  Resting Memory CD8+ T Cells are Hyperreactive to Antigenic Challenge In Vitro , 1996, The Journal of experimental medicine.

[32]  J. Goverman,et al.  T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. , 1994, Science.

[33]  H. Wallny,et al.  Soluble mouse major histocompatibility complex class II molecules produced in Drosophila cells , 1995, European journal of immunology.

[34]  K. Horgan,et al.  Hyporesponsiveness of “naive” (CD45RA+) human T cells to multiple receptor‐mediated stimuli but augmentation of responses by co‐stimuli , 1990, European journal of immunology.

[35]  M. Croft,et al.  Naive and effector CD4 T cells differ in their requirements for T cell receptor versus costimulatory signals. , 1996, Journal of immunology.

[36]  A. Lanzavecchia,et al.  Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton , 1995, The Journal of experimental medicine.

[37]  A. Abbas,et al.  The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance. , 1996, Immunity.

[38]  G. Crabtree,et al.  Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression , 1996, Nature.

[39]  C. Ruedl,et al.  Phenotypic and functional characterization of CD11c+ dendritic cell population in mouse Peyer's patches , 1996, European journal of immunology.