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

IN mammals, the genetic basis of sex determination and differentiation seems to be simple1,2. A gene or set of genes on the Y chromosome causes the indifferent embryonic gonad to develop as a testis3. Thus an ovary develops in the absence of the Y and a testis in its presence. The testis then secretes testosterone which induces male development of the accessory glands and ducts4,5. The masculinising action of testosterone on its target cells is mediated by the product of a gene on the X chromosome. This product activates all the genes required for manifestation of the male phenotype in response to circulating testosterone1. Evidence for this crucial involvement of the X chromosome in male sexual differentiation comes from a mutation of the relevant gene in the mouse (Tfm), resulting in failure to respond to testosterone. A chromosomally XY animal with this mutant gene develops testes, because the Y chromosome is present, but shows no further male differentiation, thus exhibiting the syndrome known as ‘testicular feminisation’6. This insensitivity to androgen is caused by a mutational deficiency of the nuclear–cytosol androgen-receptor protein not only in mice7–9 but also in man10. Thus the part that the X chromosome plays in male sexual differentiation has been clarified at the level of an individual gene situated on this chromosome.

Possible role for H--Y antigen in the primary determination of sex.

In man, the specific chromosome that carries each of about 210 gene loci is known. These loci include at least one assigned to each chromosome (including the Y), about 110 assigned to specific autosomes, and about 100 to the X chromosome. For many loci, information on regional chromosomal localization is also available. The information comes mainly from studies in families and somatic cell hybrids, as well as an intgratsight of results from the two methods. Knowledge of the chromosome map gives insight into evolution, chromosomal organization in relation to genetic control mechanisms, and the pathogenesis of neoplasms and malformations. Furthermore, it is useful in prenatal or premorbid diagnosis of hereditary diseases.

https://science.sciencemag.org/content/sci/196/4288/390.full.pdf

The status of the gene map of the human chromosomes

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

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

A procedure has been developed to examine the interspecies crossreactivity of the histocompatible-Y antigens (H-Y) of the sperm cells from males of different mammalian species. The test animals were inbred B6 and BALB/c mice inbred W/Fu rats inbred Strain-13 guinea pigs and Hare Rabbits. Cell suspensions were prepared from mouse epididymal sperm. The leukocyte suspensions were from mouse rat guinea pig and rabbit spleen and mesenteric lymph nodes. Human leukocyte and erytocyte suspensions were also prepared. Female adult B6 and BALB mice were immunized at least three times weekly intraperitoneally to produce H-Y- antisera. Serological testing was by the mixed hemadsorption hybrid antibody test (MHAHA) using anti-sheep erythrocyte/anti-mouse Ig for the hybrid antibody. The cytotoxicity test employed BALB epididymal sperm basically after the method of E. H. Goldberg et al. The results demonstrated an antigenic relationship of the H-Y components of the rat guinea pig rabbit and of man to those of the mouse. The H-Y antigen identical or crossreacting with mouse H-Y occurred on the male cells of all four tested species. In every case absorption with male cells reduced the number of rosettes to the background levels but this did not occur with female cells. The cytotoxicity test showed that absorption with male cells in every case removed or greatly reduced the cytotoxic activity against BALB sperm; with female cells this was not the case. These results suggest that most or all mammalian species may have H-Y antigen in common. The MHAHA technique has been demonstrated as a direct test for crossreactivity with mouse H-Y.

M. P. Scheid

Papers

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

Serological crossreactivity between H-Y (male) antigens of mouse and man (histocompatibility-Y antigen/cytotoxicity tests/mammals).