Role of Antigen-Presenting Cells in Mediating Tolerance and Autoimmunity

The mechanisms that determine whether receptor stimulation leads to lymphocyte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic β-islet cells together with T cells expressing an LCMV-gp–specific T cell receptor to assess the requirements for the induction of autoimmunity. Our studies have shown that administration of the gp peptide gp33 leads to the activation of P14-transgenic T cells, as measured by the upregulation of activation markers and the induction of effector cytotoxic activity. This treatment also leads to expansion and deletion of P14 T cells. Despite the induction of cytotoxic T lymphocyte activity, peptide administration is not sufficient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These findings suggest that the induction of tolerance versus autoimmunity is determined by resting versus activated antigen-presenting cells.

[1]  V. Kronin,et al.  Dendritic cells and T lymphocytes: developmental and functional interactions. , 2007, Ciba Foundation symposium.

[2]  C. Benoist,et al.  Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. , 1999, Science.

[3]  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.

[4]  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.

[5]  Mamoru Ito,et al.  Interleukin 12-dependent interferon gamma production by CD8alpha+ lymphoid dendritic cells. , 1999 .

[6]  R. Germain,et al.  Analysis of adjuvant function by direct visualization of antigen presentation in vivo: endotoxin promotes accumulation of antigen-bearing dendritic cells in the T cell areas of lymphoid tissue. , 1999, Journal of immunology.

[7]  Carol Kim,et al.  CD40 activation boosts T cell immunity in vivo by enhancing T cell clonal expansion and delaying peripheral T cell deletion. , 1999, Journal of immunology.

[8]  B. Pulendran,et al.  Prevention of Peripheral Tolerance by a Dendritic Cell Growth Factor: Flt3 Ligand as an Adjuvant , 1998, The Journal of experimental medicine.

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

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

[11]  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.

[12]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[13]  H. Pircher,et al.  Viral and Bacterial Infections Interfere with Peripheral Tolerance Induction and Activate CD8+ T Cells to Cause Immunopathology , 1998, The Journal of experimental medicine.

[14]  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.

[15]  P. De Baetselier,et al.  Regulation of Dendritic Cell Numbers and Maturation by Lipopolysaccharide in Vivo , 1996 .

[16]  A. Rolink,et al.  The SCID but Not the RAG-2 Gene Product Is Required for Sμ–Sε Heavy Chain Class Switching , 1996 .

[17]  James M. Wilson,et al.  CD40 Ligand-Dependent T Cell Activation: Requirement of B7-CD28 Signaling Through CD40 , 1996, Science.

[18]  J. Miller,et al.  Constitutive class I-restricted exogenous presentation of self antigens in vivo , 1996, The Journal of experimental medicine.

[19]  A. Lanzavecchia,et al.  Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation , 1996, The Journal of experimental medicine.

[20]  J. Berzofsky,et al.  Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL , 1996, The Journal of experimental medicine.

[21]  R. Schwartz,et al.  Models of T Cell Anergy: Is There a Common Molecular Mechanism? , 1996 .

[22]  K. Lafferty,et al.  Pancreatic Islet Allograft Immunity and Tolerance: the Two‐Signal Hypothesis Revisited , 1996, Immunological reviews.

[23]  P. Linsley,et al.  Lipopolysaccharide interferes with the induction of peripheral T cell death. , 1995, Immunity.

[24]  J. Banchereau,et al.  Activation of human dendritic cells through CD40 cross-linking , 1994, The Journal of experimental medicine.

[25]  Susumu Tonegawa,et al.  High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice , 1994, Cell.

[26]  C. Benoist,et al.  Following a diabetogenic T cell from genesis through pathogenesis , 1993, Cell.

[27]  Hans Hengartner,et al.  T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides , 1993, European journal of immunology.

[28]  K P Lee,et al.  Differential T cell costimulatory requirements in CD28-deficient mice. , 1993, Science.

[29]  L. Hood,et al.  Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity , 1993, Cell.

[30]  E. Shevach,et al.  Infection breaks T-cell tolerance , 1992, Nature.

[31]  H. Pircher,et al.  Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice , 1991, Cell.

[32]  J. Sprent,et al.  Extrathymic tolerance of mature T cells: Clonal elimination as a consequence of immunity , 1990, Cell.

[33]  H. Pircher,et al.  Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen , 1989, Nature.

[34]  D. E. Parks,et al.  Bacterial lipopolysaccharide (endotoxin) interferes with the induction of tolerance and primes thymus-derived lymphocytes. , 1981, Journal of immunology.

[35]  J. Chiller,et al.  TERMINATION OF TOLERANCE TO HUMAN GAMMA GLOBULIN IN MICE BY ANTIGEN AND BACTERIAL LIPOPOLYSACCHARIDE (ENDOTOXIN) , 1973, The Journal of experimental medicine.

[36]  R. Flavell,et al.  CD40 and CD154 in cell-mediated immunity. , 1998, Annual review of immunology.

[37]  B. Fazekas de St. Groth,et al.  The evolution of self-tolerance: a new cell arises to meet the challenge of self-reactivity. , 1998, Immunology today.

[38]  A. Rolink,et al.  The SCID but not the RAG-2 gene product is required for S mu-S epsilon heavy chain class switching. , 1996, Immunity.

[39]  P. Matzinger.  Tolerance, danger, and the extended family. , 1994, Annual review of immunology.

[40]  Cees van Kooten,et al.  Activation os Human Dendritic Cells through CD40 Cross-I;nking By Christophe Caux, Catherine Massacrier, B6atrice Vanbervliet, , 1994 .

[41]  C. Janeway,et al.  The immune system evolved to discriminate infectious nonself from noninfectious self. , 1992, Immunology today.

[42]  K. Lafferty,et al.  Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. , 1983, Annual review of immunology.