Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses.

A major challenge for immunologists is to explain how the immune system adjusts its responses to the microenvironmental context in which antigens are recognized. We propose that lymphocytes achieve this by tuning and updating their responsiveness to recurrent signals. In particular, cellular anergy in vivo is a dynamic state in which the threshold for a stereotypic mode of activation has been elevated. Anergy is associated with other forms of cellular activity, not paralysis. Cells engaged in such subthreshold interactions mediate functions such as maintenance of immunological memory and control of infections. In such interactions, patterns of signals are recognized and classified and evoke selective responses. The robust mechanism proposed for segregation of suprathreshold and subthreshold immune responses allows lymphocytes to use recognition of self-antigens in executing physiological functions. Autoreactivity is allowed where it is dissociated from uncontrolled aggression.

[1]  Z. Grossman Recognition of self, balance of growth and competition: Horizontal networks regulate immune responsiveness , 1982, European journal of immunology.

[2]  H. Blau,et al.  Differentiation requires continuous regulation , 1991, The Journal of cell biology.

[3]  A. Coutinho,et al.  Proliferative T cell anergy to MIs-1a does not correlate with in vivo tolerance. , 1991, International immunology.

[4]  M. Ascher,et al.  AIDS as immune system activation. II. The panergic imnesia hypothesis. , 1990, Journal of acquired immune deficiency syndromes.

[5]  K. Rajewsky,et al.  Generation and analysis of interleukin-4 deficient mice. , 1991, Science.

[6]  M. Sporn,et al.  Peptide growth factors are multifunctional , 1988, Nature.

[7]  H. von Boehmer,et al.  Self-nonself discrimination by T cells. , 1990, Science.

[8]  M. Kirschner,et al.  Beyond self-assembly: From microtubules to morphogenesis , 1986, Cell.

[9]  J. Sprent,et al.  Function and specificity of T cell subsets in the mouse. , 1987, Advances in immunology.

[10]  T. Dexter,et al.  Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis , 1990, Nature.

[11]  F E Bloom,et al.  The functional significance of neurotransmitter diversity. , 1984, The American journal of physiology.

[12]  F. Ramsdell,et al.  Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance. , 1990, Science.

[13]  I. Horak,et al.  Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting , 1991, Nature.

[14]  P. Marrack,et al.  The role of the T cell receptor in positive and negative selection of developing T cells. , 1990, Science.

[15]  R. Flavell,et al.  Tolerance in transgenic mice expressing major histocompatibility molecules extrathymically on pancreatic cells. , 1990, Science.

[16]  E. Unanue,et al.  The costimulatory function of antigen-presenting cells. , 1990, Immunology today.

[17]  P. Beverley,et al.  Is T-cell memory maintained by crossreactive stimulation? , 1990, Immunology today.

[18]  A. Coutinho,et al.  Beyond Clonal Selection and Network , 1989, Immunological reviews.

[19]  Z. Grossman,et al.  Tumor escape from immune elimination. , 1980, Journal of theoretical biology.

[20]  Defining protective responses to pathogens: cytokine profiles in leprosy lesions. , 1991, Science.

[21]  H. Kishi,et al.  Development of the CD4 and CD8 lineage of T cells: instruction versus selection. , 1991, The EMBO journal.

[22]  Z. Grossman,et al.  Recognition of Self and Regulation of Specificity at the Level of Cell Populations , 1984, Immunological reviews.

[23]  C. Janeway Approaching the asymptote? Evolution and revolution in immunology. , 1989, Cold Spring Harbor symposia on quantitative biology.

[24]  J. Sprent,et al.  T cell reactivity to MHC molecules: immunity versus tolerance. , 1990, Science.