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Journal ArticleDOI

Thymus and Lymphohemopoietic Cells: Their Role in T Cell Maturation in Selection of T Cells' H-2-Restriction-Specificity and in H-2 Linked Ir Gene Control

R. M. Zinkernagel1
01 Dec 1978-Immunological Reviews (Blackwell Publishing Ltd)-Vol. 42, Iss: 1, pp 224-270
About: This article is published in Immunological Reviews.The article was published on 1978-12-01. It has received 285 citations till now. The article focuses on the topics: T cell.
Citations
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Book ChapterDOI
TL;DR: This chapter focuses on the important discovery that virus-specific cytotoxic T cells are dually specific for virus and for a self cell surface antigen encoded by the major histocompatibility complex (MHC).
Abstract: Publisher Summary This chapter focuses on the important discovery that virus-specific cytotoxic T cells are dually specific for virus and for a self cell surface antigen encoded by the major histocompatibility complex (MHC). The initial work was carried out on the lymphocytic choriomeningitis virus system but it soon became evident that the same phenomenon applied to many other viruses. In addition, the same principle has been found to hold for other antigenic systems, such as trinitrophenyl coupled to cells, minor histocompatibility antigens, and the H-Y model. Graft rejection and the need for genetically homogeneous inbred mouse strains for cancer research led to the development of transplantation immunology and immunogenetics. The result is that the gene complex coding for major transplantation antigens is one of the better understood mammalian genetic regions. Cytotoxic T-cell specificity is comparable to serological specificity. Because quantification of specificity or cross-reactivity is difficult, and because of the technical limitations of these cytotoxic T-cell assays, results are interpreted with great reservation. MHC restriction reflects the fact that the effector function of T cells is determined by the kind of Self-H recognized together with the foreign antigen on cell surfaces: K and D are receptors for lytic signals, I determinants are receptors for cell differentiation signals that are delivered antigen-specifically by T cells.

1,858 citations

Journal ArticleDOI
TL;DR: These lines were found to recognize foreign or self antigens in association with accessory cells of syngeneic major histocompatibility complex genotype and it is possible to study biological function as well as antigen specificity using T cell lines.
Abstract: The isolation and propagation of functional antigen-specific lines of T lymphoblasts is described. These lines were found to recognize foreign or self antigens in association with accessory cells of syngeneic major histocompatibility complex genotype. Intravenous inoculation of a T cell reactive only against myelin basic protein led to development of clinical paralysis in syngeneic rats. Thus, it is possible to study biological function as well as antigen specificity using T cell lines.

931 citations

Book
01 Jan 1972
TL;DR: The house mouse is a small, slender rodent that has a slightly pointed nose; small, black, somewhat protruding eyes; large, scantily haired ears, and a nearly hairless tail with obvious scale rings.
Abstract: Identification: The house mouse (Mus musculus) is a small, slender rodent that has a slightly pointed nose; small, black, somewhat protruding eyes; large, scantily haired ears, and a nearly hairless tail with obvious scale rings. The adult mouse weighs about 2/5 to 4/5 ounces. They are generally grayish-brown with a gray or buff belly. Similar mice include the white-footed mice and jumping mice (which have a white belly), and harvest mice (which have grooved upper incisor teeth.) Native to central Asia, this species arrived in North America along with settlers from Europe and other points of origin. A very adaptable species, the house mouse often lives in close association with humans and therefore is termed one of the "commensal" rodents along with Norway and roof rats. Following their arrival on colonists’ ships, house mice spread across North America and now are found in every state including coastal areas of Alaska, and in the southern parts of Canada.

763 citations

Journal ArticleDOI
TL;DR: Intathymic injection of fluorescein isothiocyanate is used to label thymocytes in situ and so can be used to quantitate the extent of migration of cells from the thymus to the periphery.
Abstract: We have used intrathymic injection of fluorescein isothiocyanate to label thymocytes in situ. The method gives random labeling of the thymocyte population and so can be used to quantitate the extent of migration of cells from the thymus to the periphery. Migrant cells can be visualized in frozen sections or cell suspensions of peripheral organs by their fluorescence. Our data show that in young adults, about 1% of thymocytes leave the thymus per day. Since the bulk of thymocytes turn over every 5 to 7 days, this indicates that the vast majority (95%) of thyrnocytes die within the thymus. Cells that do leave the thymus, go mainly to the T areas of lymph nodes, spleen and Peyer's patches. Migrants are extremely rare in bone marrow, gut and liver. Migration is about the same in neonates as in adults relative to the size of the thymus, but is considerably lower in older animals where it is only about 0.1% of thymocytes per day at the age of six months.

549 citations

Journal Article
TL;DR: The authors showed that host H-2 antigens do exert an effect on the specificity of T-cell responses, and that CTL from a normal mouse can respond quantitatively as well to antigen plus foreign H 2 in addition to self H 2.
Abstract: CELL membrane structures controlled by genes in the major histocompatibility complex (H–2 in mice) are involved in most immune interactions between T lymphocytes and other cells1. Cytotoxic T lymphocytes (CTL) immunised against viruses2, haptens3, minor histocompatibility antigens4 or tumour antigens5, are specific for self H–2 antigens as well as for the foreign antigen. But CTL are not restricted to recognising antigens in combination with only self H–2. H–2d homozygous CTL which have matured in an irradiated H–2d/H–2k host can respond to antigen plus H–2k in addition to antigen plus H–2d (refs 6–8). It is not known whether the H–2 environment in which T cells mature influences their range of specificity, that is, whether CTL from a normal mouse can respond quantitatively as well to antigen plus foreign H–2 as they do to antigen plus self H–2. These experiments were designed to test this influence. The results suggest that host H–2 antigens do exert an effect on the specificity of T-cell responses.

489 citations

References
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Journal ArticleDOI
03 Oct 1953-Nature
TL;DR: In this article, the problem of how to make tissue homografts immunologically acceptable to hosts which would normally react against them has been studied in the context of early foetal life inoculation.
Abstract: The experiments to be described in this article provide a solution—at present only a ‘laboratory’ solution—of the problem of how to make tissue homografts immunologically acceptable to hosts which would normally react against them. The principle underlying the experiments may be expressed in the following terms: that mammals and birds never develop, or develop to only a limited degree, the power to react immunologically against foreign homologous tissue cells to which they have been exposed sufficiently early in foetal life. If, for example, a foetal mouse of one inbred strain (say, CBA) is inoculated in utero with a suspension of living cells from an adult mouse of another strain (say, A), then, when it grows up, the CBA mouse will be found to be partly or completely tolerant of skin grafts transplanted from any mouse belonging to the strain of the original donor. This phenomenon is the exact inverse of ‘actively acquired immunity’, and we therefore propose to describe it as ‘actively acquired tolerance’. The distinction between the two phenomena may be made evident in the following way. If a normal adult CBA mouse is inoculated with living cells or grafted with skin from an A-line donor, the grafted tissue is destroyed within twelve days (see below). The effect of this first presentation of foreign tissue in adult life is to confer ‘immunity’, that is, to increase the host’s resistance to grafts which may be transplanted on some later occasion from the same donor or from some other member of the donor’s strain. But if the first presentation of foreign cells takes place in foetal life, it has just the opposite effect: resistance to a graft transplanted on some later occasion, so far from being heightened, is abolished or at least reduced. Over some period of its early life, therefore, the pattern of the host’s response to foreign tissue cells is turned completely upside down. In mice, it will be seen, this inversion takes place in the neighbourhood of birth, for there is a certain ‘null’ period thereabouts when the inoculation of foreign tissue confers neither tolerance nor heightened resistance—when, in fact, a ‘test graft’ transplanted in adult life to ascertain the host’s degree of immunity is found to survive for the same length of time as if the host had received no treatment at all.

2,867 citations

Journal ArticleDOI
21 Jan 1972-Science
TL;DR: The chapter presents a description of the specific immune responses that are under the control of H-linked Ir genes in guinea pigs, mice, and rats.
Abstract: Publisher Summary This chapter provides information on histocompatibility-linked immune response genes. The genetic study of the capacity to form specific immune responses has revealed that the recognition of antigens as immunogens by individual animals and inbred strains is governed by the product of individual dominant genes located in the genome in close relationship with the genes coding for the molecules bearing the major histocompatibility specificities. These genes are termed as “histocompatibility,” or “H-linked Ir genes.” The presence of relevant genes permit immune responses to be formed, characterized by cellular immunity and antibody synthesis against the determinants on the antigens concerned. Three types of antigens are most useful in the identification of H-linked Ir genes: (1) synthetic polypeptides with limited structural heterogeneity; (2) alloantigens that differ slightly from their autologous counterparts, and (3) complex multideterminants antigens administered in limiting immunizing doses in conditions where only the most immunogenic determinants are recognized. Thus, the discovery of specific H-linked Ir genes depends upon experiments wherein the immunological system is presented with a challenge of highly restricted heterogeneity and specificity. The chapter presents a description of the specific immune responses that are under the control of H-linked Ir genes in guinea pigs, mice, and rats.

1,171 citations

Book ChapterDOI
TL;DR: Specific cell-mediated cytotoxicity in vitro can be divided into three categories according to the nature of the effector cells, which is most often highly specific and requires intimate contact rather than release of diffusible toxic factors.
Abstract: Publisher Summary The term “cell-mediated cytotoxicity” applies to lytic reactions that require the participation of lymphoid or non-lymphoid cells but not of added complement. It has been clearly established that several pathways, including different cell types, are involved in cytotoxic reactions in vitro. With membrane-associated antigens, such as transplantation, and tumor-associated antigens, the cytotoxic effect of effector cells on adequate target cells is most often highly specific and requires intimate contact rather than release of diffusible toxic factors. Specific cell-mediated cytotoxicity in vitro can be divided into three categories according to the nature of the effector cells.

1,107 citations

Journal ArticleDOI
TL;DR: It has been shown that the immune response of mice to infection with L. monocytogenes gives rise to a population of immunologically committed lymphoid cells which have the capacity to confer protection and a proportionate level of delayed-type hypersensitivity upon normal recipients.
Abstract: It has been shown that the immune response of mice to infection with L. monocytogenes gives rise to a population of immunologically committed lymphoid cells which have the capacity to confer protection and a proportionate level of delayed-type hypersensitivity upon normal recipients. The cells were most numerous in the spleen on the 6th or 7th day of infection, but persisted for at least 20 days. Further study revealed that the immune cells must be alive in order to confer protection, and free to multiply in the tissues of the recipient if they are to provide maximum resistance to a challenge infection. The antibacterial resistance conferred with immune lymphoid cells is not due to antibacterial antibody; it is mediated indirectly through the macrophages of the recipient. These become activated by a process which appears to depend upon some form of specific interaction between the immune lymphoid cells and the infecting organism. This was deduced from the finding that immune lymphoid cells from BCG-immunized donors, which were highly but nonspecifically resistant to Listeria, failed to protect normal recipients against a Listeria challenge unless the recipients were also injected with an eliciting dose of BCG. The peritoneal macrophages of animals so treated developed the morphology and microbicidal features of activated macrophages. It is inferred that acquired resistance depends upon the activation of host macrophages through a product resulting from specific interaction between sensitized lymphoid cells and the organism or or its antigenic products. Discussion is also made of the possibility that activation of macrophages could be dependent upon antigenic stimulation of macrophages sensitized by a cytophilic antibody.

914 citations

Journal ArticleDOI
TL;DR: The present hypothesis proposes that the germ‐cells of an animal carry a set of v‐genes determining the combining sites of antibodies directed against a complete set of a certain class of histocompatibility antigens of the species to which this animal belongs.
Abstract: Antibody specificity is determined by structural v-genes that code for the amino acid sequences of the variable regions of antibody polypeptide chains. The present hypothesis proposes that the germ-cells of an animal carry a set of v-genes determining the combining sites of antibodies directed against a complete set of a certain class of histocompatibility antigens of the species to which this animal belongs. The evolutionary development of this set of v-genes in phylogeny is traced back to the requirements for cell to cell recognition in all metazoa. The hypothesis leads to a distinction between two populations of antigen-sensitive cells. One population consists of cells forming antibodies against foreign antigens; these lymphocytes have arisen as mutants in clones descending from lymphocytic stem cells which expressed v-genes belonging to the subset (subset S) coding for antibody against histocompatibility antigens that the individual happens to possess. The other population consists of allograft rejecting lymphocytes that express v-genes of the remaining subset (subset A) coding for antibody against histocompatibility antigens of the species that the individual does not possess. The primary lymphoid organs are viewed as mutant-breeding organs. In these organs (e. g. in the thymus), the proliferation of lymphocytes expressing the v-genes of subset S and the subsequent suppression of the cells of these “forbidden” clones, leads to the selection of mutant cells expressing v-genes that have been modified by spontaneous random somatic mutation. This process generates self-tolerance as well as a diverse population of antigen-sensitive cells that reflects antibody diversity. The proliferation in the primary lymphoid organs of lymphocytes expressing v-genes of subset A generates the antigen-sensitive cell population that is responsible for allo-aggression. The theory explains how a functional immune system can develop through a selection pressure exerted by self-antigens, starting during a period in early ontogeny that precedes clonal selection by foreign antigens. The hypothesis provides explanations for the variability of the N-terminal regions of antibody polypeptide chains, for the dominant genetic control of specific immune responsiveness by histocompatibility alleles, for the relative preponderance of antigen-sensitive cells directed against allogeneic histocompatibility antigens, for antibody-idiotypes, for allelic exclusion, for the precommitment of any given antigen-sensitive lymphocyte to form antibodies of only one molecular species and for the cellular dynamics in the primary lymphoid tissues.

859 citations