Naïve CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation

In defense of the host, the immune system must often raise an effective cytotoxic T lymphocyte (CTL) response from a small number of clonal precursors. The degree to which activation stimuli regulate the expansion and differentiation of naïve CTLs, however, remains unknown. Using an engineered antigen-presenting cell (APC) system that allows control over antigenic stimulation, we studied the signaling duration requirements for priming and clonal expansion of naïve CTLs. We found that naïve CTLs become committed after as little as 2 h of exposure to APCs and that their subsequent division and differentiation can occur without the need for further antigenic stimulation of the daughter cells, whether priming is in vitro or in vivo. These data show that after a brief interaction with stimulatory APCs, naïve CTLs initiate a program for their autonomous clonal expansion and development into functional effectors.

[1]  H. Bien,et al.  Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40 , 1999, Nature Medicine.

[2]  A. Lanzavecchia,et al.  T lymphocyte costimulation mediated by reorganization of membrane microdomains. , 1999, Science.

[3]  Henrique Veiga-Fernandes,et al.  Response of naïve and memory CD8+ T cells to antigen stimulation in vivo , 2000, Nature Immunology.

[4]  Stefania Gallucci,et al.  Natural adjuvants: Endogenous activators of dendritic cells , 1999, Nature Medicine.

[5]  L. Wang,et al.  Expression of the T cell antigen receptor zeta chain following activation is controlled at distinct checkpoints. Implications for cell surface receptor down-modulation and re-expression. , 1999, The Journal of biological chemistry.

[6]  P. Brown,et al.  Genomic views of the immune system*. , 2000, Annual review of immunology.

[7]  C. Kurts,et al.  Cross-tolerance: A Pathway for Inducing Tolerance to Peripheral Tissue Antigens , 1998, The Journal of experimental medicine.

[8]  J. Hutchcroft,et al.  CD28/CTLA-4 and CD80/CD86 families , 1999, Immunologic research.

[9]  A. Sharpe,et al.  Either B7 Costimulation or IL-2 Can Elicit Generation of Primary Alloreactive CTL1 , 2000, The Journal of Immunology.

[10]  S. Swain,et al.  Lymphokines and the immune response: the central role of interleukin-2. , 1991, Current opinion in immunology.

[11]  M. Kuroda,et al.  Functional Equivalency of B7-1 and B7-2 for Costimulating Plasmid DNA Vaccine-Elicited CTL Responses1 , 2000, The Journal of Immunology.

[12]  A. B. Lyons,et al.  Divided we stand: Tracking cell proliferation with carboxyfluorescein diacetate succinimidyl ester , 1999, Immunology and cell biology.

[13]  J. Harty,et al.  CD8+ T cell effector mechanisms in resistance to infection. , 2000, Annual review of immunology.

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

[15]  A. Sharpe,et al.  B7 Costimulation Is Critical for Antibody Class Switching and CD8+ Cytotoxic T-Lymphocyte Generation in the Host Response to Vesicular Stomatitis Virus , 2000, Journal of Virology.

[16]  F. Sallusto,et al.  From synapses to immunological memory: the role of sustained T cell stimulation. , 2000, Current opinion in immunology.

[17]  J. Altman,et al.  In vivo dynamics of anti-viral CD8 T cell responses to different epitopes. An evaluation of bystander activation in primary and secondary responses to viral infection. , 1998, Advances in experimental medicine and biology.

[18]  Kristin A. Hogquist,et al.  T cell receptor antagonist peptides induce positive selection , 1994, Cell.

[19]  M. Bevan,et al.  Antigen presentation to cytotoxic T lymphocytes in vivo , 1995, The Journal of experimental medicine.

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

[21]  S. Swain,et al.  Two Distinct Stages in the Transition from Naive CD4 T Cells to Effectors, Early Antigen-Dependent and Late Cytokine-Driven Expansion and Differentiation1 , 2000, The Journal of Immunology.

[22]  A. Lanzavecchia.  From antigen presentation to T-cell activation. , 1998, Research in Immunology.

[23]  Nina Bhardwaj,et al.  Consequences of cell death: exposure to necrotic tumor cells , 2000 .

[24]  L. Nguyen,et al.  Role of Antigen-Presenting Cells in Mediating Tolerance and Autoimmunity , 2000, The Journal of experimental medicine.

[25]  E. Simpson,et al.  B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. , 1997, Immunity.

[26]  R. Offringa,et al.  Efficient direct priming of tumor-specific cytotoxic T lymphocyte in vivo by an engineered APC. , 1998, Cancer research.

[27]  C. Kurts,et al.  Class I–restricted Cross-Presentation of Exogenous Self-Antigens Leads to Deletion of Autoreactive CD8+ T Cells , 1997, The Journal of experimental medicine.

[28]  M. Bevan,et al.  Role of self-peptides in positively selecting the T-cell repertoire , 1990, Nature.

[29]  A. Lanzavecchia,et al.  The duration of antigenic stimulation determines the fate of naive and effector T cells. , 1998, Immunity.

[30]  A. Lanzavecchia.  Dendritic cell maturation and generation of immune responses. , 1999, Haematologica.

[31]  M. Jackson,et al.  T Cells Can Use Either T Cell Receptor or Cd28 Receptors to Absorb and Internalize Cell Surface Molecules Derived from Antigen-Presenting Cells , 2000, The Journal of experimental medicine.

[32]  M. Jackson,et al.  TCR-Mediated internalization of peptide-MHC complexes acquired by T cells. , 1999, Science.

[33]  J. Forman,et al.  Helper activity is required for the in vivo generation of cytotoxic T lymphocytes , 1982, The Journal of experimental medicine.

[34]  P. Srivastava,et al.  Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. , 2000, International immunology.

[35]  N. Shastri,et al.  Measurement of ligand-induced activation in single viable T cells using the lacZ reporter gene. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[36]  B. Alarcón,et al.  Triggering the TCR complex causes the downregulation of nonengaged receptors by a signal transduction-dependent mechanism. , 2000, Immunity.

[37]  Richard A. Flavell,et al.  Help for cytotoxic-T-cell responses is mediated by CD40 signalling , 1998, Nature.

[38]  Polly Matzinger,et al.  A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell , 1998, Nature.

[39]  K. Lafferty,et al.  A new analysis of allogeneic interactions. , 1975, The Australian journal of experimental biology and medical science.

[40]  W. Heath,et al.  Induction of a CD8+ Cytotoxic T Lymphocyte Response by Cross-priming Requires Cognate CD4+ T Cell Help , 1997, The Journal of experimental medicine.

[41]  Stephen P. Schoenberger,et al.  T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions , 1998, Nature.

[42]  P. Matzinger.  The JAM test. A simple assay for DNA fragmentation and cell death. , 1991, Journal of immunological methods.

[43]  Hanno Langen,et al.  Maturation, Activation, and Protection of Dendritic Cells Induced by Double-stranded RNA , 1999, The Journal of experimental medicine.

[44]  N. Shastri,et al.  LacZ inducible, antigen/MHC-specific T cell hybrids. , 1994, International immunology.

[45]  P. Srivastava,et al.  Cutting Edge: Heat Shock Protein gp96 Induces Maturation and Migration of CD11c+ Cells In Vivo1 , 2000, The Journal of Immunology.

[46]  I. Maclennan,et al.  Is rapid proliferation in B centroblasts linked to somatic mutation in memory B cell clones? , 1988, Immunology letters.

[47]  J. Altman,et al.  Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. , 1998, Immunity.