A role for perforin in activation-induced T cell death in vivo: increased expansion of allogeneic perforin-deficient T cells in SCID mice.

Despite defective granule exocytosis, T cells from mice whose perforin gene was ablated by homologous recombination (pko mice) caused a similar degree of graft-vs-host disease as normal T cells after injection into sublethally irradiated C.B-17 SCID mice. Moreover host spleens contained significantly greater numbers of T cells from pko mice than from wild-type mice following their i.v. injection. This increase could not be explained by persistence of host APCs that were not cleared by defective donor cytotoxic effector cells. The absence of functional perforin-dependent suppressor cells or an altered cytokine profile of donor T cells could also not account for the behavior of pko cells. Spontaneous and Fas-mediated apoptosis of in vivo activated donor T cells were independent of donor origin. However, pko T blasts exhibited less growth inhibition and cell death after reactivation in vitro. The results are compatible with a model of a defective activation-induced cell death (AICD) pathway, controlled by perforin, accounting for the increased expansion of alloreactive pko T cells.

[1]  J. Allison,et al.  Identification and distribution of the costimulatory receptor CD28 in the mouse. , 1992, Journal of immunology.

[2]  M. Schrenzel,et al.  Differential production of interferon-γ and interleukin-4 in response to Th1- and Th2-stimulating pathogens by γδ T cells in vivo , 1995, Nature.

[3]  B. Rocha,et al.  Peripheral selection of the T cell repertoire. , 1991, Science.

[4]  M. Battegay,et al.  Fibroblasts as efficient antigen-presenting cells in lymphoid organs. , 1995, Science.

[5]  R. Dutton,et al.  Type 1 and type 2: a fundamental dichotomy for all T-cell subsets. , 1996, Current opinion in immunology.

[6]  Z. Darżynkiewicz,et al.  Features of apoptotic cells measured by flow cytometry. , 1992, Cytometry.

[7]  P. Rubin,et al.  Early and persistent alterations in the expression of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor alpha mRNA levels in fibrosis-resistant and sensitive mice after thoracic irradiation. , 1996, Radiation research.

[8]  E. Podack.  Execution and suicide: cytotoxic lymphocytes enforce Draconian laws through separate molecular pathways. , 1995, Current opinion in immunology.

[9]  A. Coutinho,et al.  Population dynamics of T lymphocytes. Renewal rate and expansion in the peripheral lymphoid organs. , 1983, Journal of immunology.

[10]  C. Biron,et al.  Aberrant T cells in beige mutant mice. , 1987, Journal of immunology.

[11]  J. Bluestone,et al.  Identification of a monoclonal antibody specific for a murine T3 polypeptide. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[12]  H. Karasuyama,et al.  Autocrine growth and tumorigenicity of interleukin 2-dependent helper T cells transfected with IL-2 gene , 1989, The Journal of experimental medicine.

[13]  R. Miller,et al.  Peripheral tolerance through clonal deletion of mature CD4-CD8+ T cells. , 1992, International immunology.

[14]  Lianfa Shi,et al.  Premature p34cdc2 activation required for apoptosis. , 1994, Science.

[15]  S. Tonegawa,et al.  Gamma delta T cells differentiate into a functional but nonproliferative state during a normal immune response. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Dower,et al.  Tumor necrosis factor ligand superfamily: involvement in the pathology of malignant lymphomas. , 1995, Blood.

[17]  J. Ferrara,et al.  The Immunopathophysiology of Acute Graft‐Versus‐Host‐Disease , 1996, Stem cells.

[18]  T. Mak,et al.  Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection , 1993, Cell.

[19]  J. Unkeless.  Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors , 1979, The Journal of experimental medicine.

[20]  R. Zinkernagel,et al.  Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. , 1996, Annual review of immunology.

[21]  R. Welsh,et al.  Programmed cell death of T lymphocytes during acute viral infection: a mechanism for virus-induced immune deficiency , 1993, Journal of virology.

[22]  G. Mills,et al.  Cell cycle progression out of G1 sensitizes primary-cultured nontransformed T cells to TCR-mediated apoptosis. , 1996, Cellular immunology.

[23]  D. Longo,et al.  Gene complementation. Neither Ir-GLphi gene need be present in the proliferative T cell to generate an immune response to Poly(Glu55Lys36Phe9)n , 1980, The Journal of experimental medicine.

[24]  D. Green,et al.  Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl , 1995, The Journal of experimental medicine.

[25]  R. Dutton,et al.  Relative perforin- and Fas-mediated lysis in T1 and T2 CD8 effector populations. , 1995, Journal of immunology.

[26]  F. Ramsdell,et al.  Fas and FasL in the homeostatic regulation of immune responses. , 1995, Immunology today.

[27]  J. Russell,et al.  Activation-induced death of mature T cells in the regulation of immune responses. , 1995, Current opinion in immunology.

[28]  C. Smith,et al.  Activation-induced peripheral blood T cell apoptosis is Fas independent in HIV-infected individuals. , 1996, International immunology.

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

[30]  K. Baetz,et al.  Serial killing by cytotoxic T lymphocytes: T cell receptor triggers degranulation, re‐filling of the lytic granules and secretion of lytic proteins via a non‐granule pathway , 1995, European journal of immunology.

[31]  C. Ware,et al.  Human, rat or mouse hybridomas secrete high levels of monoclonal antibodies following transplantation into mice with severe combined immunodeficiency disease (SCID). , 1985, Journal of immunological methods.

[32]  A. Carroll,et al.  The SCID mouse mutant: definition, characterization, and potential uses. , 1991, Annual review of immunology.

[33]  J. Abrams,et al.  Strategies of Anti‐Cytokine Monoclonal Antibody Development: Immunoassay of IL‐10 and IL‐5 in Clinical Samples , 1992, Immunological reviews.

[34]  D. Green,et al.  Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. , 1992, Science.

[35]  G. Mills,et al.  Fas (CD95) participates in peripheral T cell deletion and associated apoptosis in vivo. , 1995, International immunology.

[36]  J. Christensen,et al.  Virus-induced polyclonal T cell activation is followed by apoptosis: partitioning of CD8+ T cells based on alpha 4 integrin expression. , 1996, International immunology.

[37]  G. Mills,et al.  CD28 costimulation inhibits TCR-induced apoptosis during a primary T cell response. , 1996, Journal of immunology.

[38]  Y. Kawabe,et al.  Programmed cell death and extrathymic reduction of Vβ8+CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B , 1991, Nature.

[39]  G. Griffiths,et al.  Structure and biogenesis of lytic granules. , 1995, Current topics in microbiology and immunology.

[40]  M. Kastan,et al.  Growth factor modulation of p53-mediated growth arrest versus apoptosis. , 1995, Genes & development.

[41]  Hans Hengartner,et al.  Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice , 1994, Nature.

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

[43]  R. Zinkernagel,et al.  Virus-specific cytotoxic T cell-mediated lysis of lymphocytes in vitro and in vivo. , 1993, Journal of immunology.

[44]  L. Chess,et al.  Murine CD8+ T cells that specifically delete autologous CD4+ T cells expressing V beta 8 TCR: a role of the Qa-1 molecule. , 1995, Immunity.

[45]  A. Whetton,et al.  Activation of the Abelson tyrosine kinase activity is associated with suppression of apoptosis in hemopoietic cells. , 1993, Cancer research.

[46]  L. Montagnier,et al.  Apoptosis in AIDS. , 1993, Science.

[47]  M. Lenardo,et al.  Induction of apoptosis in mature T cells by tumour necrosis factor , 1995, Nature.

[48]  G. Mills,et al.  Religation of the T cell receptor after primary activation of mature T cells inhibits proliferation and induces apoptotic cell death. , 1993, Journal of immunology.

[49]  C. Prives,et al.  p53: puzzle and paradigm. , 1996, Genes & development.

[50]  K. Raju,et al.  A role for perforin in activation-induced cell death. , 1998, Journal of immunology.

[51]  D. Spaner,et al.  The scid Mouse: Mutation in a DNA Repair Gene Creates Recipients Useful for Studies on Stem Cells, Lymphocyte Development and Graft‐versus‐Host Disease , 1991, Immunological reviews.