Publisher Summary The recognition of the existence of natural cell-mediated immunity, particularly natural cell-mediated cytotoxicity, has significantly altered the concepts concerning the potential mechanisms for in vivo resistance against tumor growth and for in vitro cell-mediated immune reactions. When cytotoxic reactions are measured, the evaluation of the role of natural killer (NK) cells and other more well-known mechanisms of cytotoxicity must be done carefully. This chapter focuses on natural cell-mediated cytotoxicity. It summarizes the known information on the expression of natural cytotoxicity in rodents and in man, its specificity, the nature of the effector cells and their relationship to other immune mechanisms, and the possible in vivo relevance of natural cytotoxicity, particularly in regard to resistance against tumor growth. The basic observation that initiated the studies of natural cell mediated cytotoxicity includes that lymphoid cells from some normal mice, rats, and human donors, which are not inoculated with tumor cells or other sources of antigen, exhibit significant levels of cytotoxic reactivity against certain syngeneic or allogeneic tumor cells.

Natural Cell-Mediated Immunity

A polypeptide of 8500 molecular weight is described that induces the differentiation of T (thymus-derived) cell and B (bone-marrow-derived) cell immunocytes in vitro, apparently via beta-adrenergic receptors and adenylate cyclase activation. This polypeptide shows a high degree of evolutionary conservation, exhibiting close structural, functional, and immunological similarity when isolated from such diverse origins as cells of mammals and higher plants. This polypeptide was detected in animal cells, yeast, bacteria, and higher plants, and so may well be a universal constituent of living cells.

http://www.pnas.org/content/72/1/11.full.pdf

Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells

Publisher Summary This chapter discusses the nature of endotoxins and their interactions with cells of the immune system. The direct interaction of endotoxin with B lymphocytes leading to the formation of antibodies to endotoxin as well as a spectrum of other immunoglobulin molecules is discussed. In addition, the interactions of endotoxins with T cells and macrophages and the associated immunoregulatory effects are discussed. The central role of the lipid A portion of the endotoxin molecule in cellular activation and the molecular events occurring at the cell surface in the course of stimulation are presented. The potential of endotoxins as therapeutic manipulators of the immune response in man is also evaluated. Major direct interactions of endotoxins with B lymphocytes have been documented, leading to synthesis and secretion of antibody directed not only against antigenic determinants on the endotoxin molecules themselves, but also with specificities characteristic of the complete repertoire of variable region gene products. Knowledge of the immunobiology of endotoxins has prompted investigations in their therapeutic uses in man as both antigenically distinct and cross-reactive immunogens in protection against gram-negative infections.

Bacterial endotoxins and host immune responses

Intrathymic and Extrathymic T Cell Maturation

Publisher Summary Paralysis is seriously considered only in the “two specific signal” hypothesis by postulating that the first signal, generated by the combination of antigen with the specific receptor, results in tolerance rather than induction, except if the cell is simultaneously exposed to the second specific signal, generated by the recognition of the antigen by associative antibody. This model of associative recognition is designed in order to explain self-nonself discrimination and denies the existence of truly thymus-independent (TI) antigens as well as the possibility of triggering B cells by any mechanism not involving the first specific signal. The main general conclusion concerning induction of paralysis by TI antigens is that specific B cells are turned off at higher concentrations of the TI antigen than those causing activation. TI antigens do induce specific B cells directly and one cannot exclude that at least some of them also activate other cell types, including T cells, nor that some or possibly all of them interact with macrophages. It is suggested that the effects on other cell types represent trivial or optimizing events on top of the basic, fundamentally effective mechanism of direct B-cell activation. All TI antigens are competent to activate B cells polyclonally and this nonspecific property seems to be responsible for induction of specific cells. The inactivation of competent specific cells is also a result of the interaction between nonspecific surface receptors and the competent ligand.

Thymus-independent B-cell induction and paralysis.

Summary of Experiments Showing Generation of T Cells from Precursor Cells under the Influence of Thymic and Nonthymlc Agents Material tested for inducer activity Criterion of T cell induction Source Mouse thymus Mouse spleen Description* Expression of TL or Thy-1 antigen Fr 2 (KK) Fr 2 (KK) Medium II: in I: in vitro~ nu/nu mice§ Induced cells % 20 <10 20,40 Mouse thymus Calf thymus Calf thymus Calf thymus Calf thymus Calf spleen Calf muscle Rat thymus Chicken thymus Human thymus Fr 3 Fr 2 Ft 3 5 6 Ft 3 Fr 3 Ft 2 Fr 2 Ft 3 20-23 <10 <10 m Calf thymus¶ (AG) 40-45 (KK) 20-25 (AG) 40-45 (AG) 25-30 (AG) 18-22 (AG) 40-45 (AG) 40-45 (KK) 20-25 (KK) 25-30 (AG) 25-30 20 25 20-25 15-19 < 10, < l0 25 10 30 <10 Appearance of helper effect in vitroll cAMP DB-cAMP Poly A:U Endotoxin BSA, Medium Ft 2 (KK) + Aminophylline Fr 2 (KK) + Insulin Fr 2 (KK) + Medium PFC/culture 5th exp 24 ~10 Because of space limitations, details of materials and methods can be indicated for the most part only by key references to where full descriptions can be found * Fr = fraction (KK) = fraction prepared by Dr K Komuro according to Goldstein

/pdf/differentiation-of-t-cells-induced-by-preparations-from-47poicu14g.pdf

M. K. Hoffmann

Papers

Differentiation of t cells induced by preparations from thymus and by nonthymic agents : the determined state of the precursor cell