The lymphoreticular system in triggering virus plus self-specific cytotoxic T cells: evidence for T help.
01 Mar 1978-Journal of Experimental Medicine (Rockefeller University Press)-Vol. 147, Iss: 3, pp 897-911
TL;DR: If T cells learn in the thymus to recognize H-21 or K, D markers that are not at least partially carried themselves in other cells of the lymphoreticular system immunological interactions will be impossible and this paradox situation results in phenotypic immune incompetence in vivo.
Abstract: The thymus determines the spectrum of the receptor specificities of differentiating T cells for self-H-2; however, the phenotypic expression of T cell's specificity for self plus virus is determined predominantly by the H-2 type of the antigen presenting cells of the peripheral lymphoreticular system Furthermore, virus specific helper T cells are essential for the generation of virus-specific cytotoxic T cells For cooperation between mature T cells and other lymphocytes to be functional in chimeras, thymic epithelial cells and lymphohemopoietic stem cells must share the I region; killer T-cell generation also requires in addition compatibility for at least one K or D region These conclusions derive from the following experiments: A leads to (A X B)F1 chimeric lymphocytes do produce virus-specific cytotoxic T-cell activity for infected A but not for infected B cells; when sensitized in an acutely irradiated and infected recipient (A X B)F1 these chimeric lymphocytes respond to both infected A and B Therefore the predominantly immunogenically infected cells of chimeras the radiosensitive and by donor stem cells replaced lymphoreticular cells In this adoptive priming model (KAIA/DB leads to KAIA/DC) chimeric lymphocytes could be sensitized in irradiated and infected F1 against KA and DC but not against infected DB targets In contrast KBIB/DA leads to KCIC/DA chimeras' lymphocytes could not be sensitized at all in appropriately irradiated and infected F1 recipients Thus these latter chimeras probably lack functional I-specific T helper cells that are essential for the generation of T killer cells against infected D compatible targets If T cells learn in the thymus to recognize H-21 or K, D markers that are not at least partially carried themselves in other cells of the lymphoreticular system immunological interactions will be impossible and this paradox situation results in phenotypic immune incompetence in vivo
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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
TL;DR: Experimental data are presented showing that human fetal liver hematopoietic cells, human fetal thymus, and human fetal lymph node support the differentiation of mature human T cells and B cells after engraftment into mice with genetically determined severe combined immunodeficiency.
Abstract: The study of human hematopoietic cells and the human immune system is hampered by the lack of a suitable experimental model. Experimental data are presented showing that human fetal liver hematopoietic cells, human fetal thymus, and human fetal lymph node support the differentiation of mature human T cells and B cells after engraftment into mice with genetically determined severe combined immunodeficiency. The resultant SCID-hu mice are found to have a transient wave of human CD4+ and CD8+ T cells and human IgG (immunoglobulin G) in the peripheral circulation. The functional status of the human immune system within this mouse model is not yet known.
1,470 citations
TL;DR: These findings demonstrate that the failure of an effective antitumor immune response may be primarily due to a helper arm deficiency of the immune system rather than a paucity of tumor-specific cytotoxic effector cells and outline a novel strategy for augmenting tumor immunity.
992 citations
TL;DR: In these mice, the development of CD8+ T cells and myeloid components is unaltered, indicating that expression of CD4 on progenitor cells and CD4+CD8+ (double positive) thymocytes is not obligatory, which is important to the understanding of immune disorders, including AIDS.
Abstract: T CELLS express T-cell antigen receptors (TCR) for the recognition of antigen in conjunction with the products of the major histocompatibility complex1,2. They also express two key surface coreceptors, CD4 and CDS, which are involved in the interaction with their ligands3,4. As CD4 is expressed on the early haemopoietic progenitor5 as well as the early thymic precursor cells6, a role for CD4 in haemopoiesis and T-cell development is implicated. Thymocytes undergo a series of differentiation7 and selection steps8,9 to become mature CD4+8− or CD4−8+ (single positive) T cells10,11. Studies of the role of CD4+ T cells in vivo have been based on adoptive transfer of selected or depleted lymphocytes, or in vivo treatment of thymectomized mice with monoclonal antibodies causing depletion of CD4+ T cells12–14. In order to study the role of the CD4 molecule in the development and function of lymphocytes, we have disrupted the CD4 gene in embryonic stem cells15–16 by homologous recombination17–18. Germ-line transmission19–20 of the mutation produces mutant mouse strains that do not express CD4 on the cell surface. In these mice, the development of CD8+ T cells and myeloid components is unaltered, indicating that expression of CD4 on progenitor cells and CD4+ CD8+ (double positive) thymocytes is not obligatory. Here we report that these mice have markedly decreased helper cell activity for antibody responses, although cytotoxic T-cell activity against viruses is in the normal range. This differential requirement for CD4+ helper T cells is important to our understanding of immune disorders, including AIDS, in which CD4+ cells are reduced or absent.
705 citations
TL;DR: The generation of anti-Qa-1(b) CTL is under immune response (Ir) gene control because F(1) mice, obtained by crossing responder A/J with nonresponder B6.T1a(a) animals, generated CTL to the Qa-2 alloantigen when presented on B6 spleen cells.
Abstract: B6.T1a(a) (Qa-1(a)) mice that are primed in vivo and restimulated in vitro with Qa-1 congenic spleen cells from B6 (Qa-1(b)) animals are unable to generate anti-Qa-1(b) cytotoxic T lymphocytes (CTL). This nonresponsive pattern was observed regardless of the route of immunization or the time of testing in vitro. Although B6.T1a(a) mice are nonresponders to Qa-1(b) when presented on B6 cells, these mice can generate anti-Qa-1(b) CTL when primed in vivo with Qa-1 and H-Y alloantigens (females primed with B6 male cells) or Qa-1 and minor-H- alloantigens (primed with sex-matched A.BY cells). Therefore, the inability to generate anti-Qa-1(b) CTL is due to a lack of helper or accessory antigens on B6 immunizing cells obligatory during in vivo priming, rather than an absence of anti-Qa-1(b) CTL precursors (CTL-P). Demonstration that the additional determinants required during in vivo priming actually function as carrier or helper determinants was shown by the requirement for linked recognition of Qa-1 and the helper determinants (H-Y) in vivo, and the fact that H-Y was not present on susceptible target ceils. Animals primed in vivo with H-Y only could not generate anti-Qa-1 CTL activity when challenged in vitro with both Qa-1 and H-Y, indicating that recognition of the helper determinant causes in vivo priming of CTL-P rather than generating helper activity that might activate unprimed CTL-P in vitro. Whereas unprimed peripheral CTL-P require the presence of both Qa-1 (CTL) and H-Y (helper) determinants for successful in vivo priming, helper determinants were not required in vitro because primed CTL-P from B6.T1a(a) mice could be driven to CTL in vitro using sex-matched B6 stimulator cells. The generation of anti-Qa-1(b) CTL is under immune response (Ir) gene control because F(1) mice, obtained by crossing responder A/J with nonresponder B6.T1a(a) animals, generated CTL to the Qa-1(b) alloantigen when presented on B6 spleen cells. Progeny testing of backcross mice further demonstrated that the Ir gene(s) is linked to the H-2 complex. These data indicate that an H-2-linked Ir gene controls the recognition of helper determinants required for CTL priming in vivo. These helper determinants can be distinguished from CTL determinants and both must be recognized together for successful priming of CTL-P.
533 citations
Cites background from "The lymphoreticular system in trigg..."
...(15) and von Boehmer and Haas (16), who showed, using bone marrow repopulated radiation chimeras, that there is a requirement for I region sharing between CTL and radiation-resistant thymus cells to generate antiviral and anti-H-Y effector cell activity....
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...(15) and von Boehmer and Haas (16), using bone marrowreconstituted radiation chimeras, showed a necessity for I region sharing between...
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References
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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
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
Additional excerpts
...ZINKERNAGEL, CALLAHAN, ALTHAGE, COOPER, STREILEIN, AND KLEIN 909 raised previously ( 33-37 )....
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TL;DR: Adult thymectomized, irradiated and bone marrow reconstituted mice, transplanted with an irradiated thymus of A origin, generate virus-specific cytotoxic T cells specific for infected A targets but not for B targets; this result formally demonstrates the crucial role of thymic epithelial cells in the differentiation of anti-self-H-2 specificities of T cells.
Abstract: In the thymus, precursor T cells differentiate recognition structures for self that are specific for the H-2K, D, and I markers expressed by the thymic epithelium. Thus recognition of self-H-2 differentiates independently of the T cells H-2 type and independently of recognition of nonself antigen X. This is readily compatible with dual recognition by T cells but does not formally exclude a single recognition model. These conclusions derive from experiments with bone marrow and thymic chimeras. Irradiated mice reconstituted with bone marrow to form chimeras of (A X B)F1 leads to A type generate virus-specific cytotoxic T cells for infected targets A only. Therefore, the H-2 type of the host determines the H-2-restricted activity of killer T cells alone. In contrast, chimeras made by reconstituting irradiated A mice with adult spleen cells of (A X B)F1 origin generate virus-specific cytotoxic activity for infected A and B targets, suggesting that mature T cells do not change their self-specificity readily. (A X B)F1 leads to (A X C)F1 and (KAIA/DC) leads to (KAIA/DB) irradiation bone marrow chimeras responded against infected A but not B or C targets. This suggests that cytotoxicity is not generated against DC because it is abscent from the host's thymus epithelium and not against DB because it is not expressed by the reconstituting lymphoreticular system. (KBIB/DA) leads to (KCIC/DA) K, I incompatible, or completely H-2 incompatible A leads to B chimeras fail to generate any measurable virus specific cytotoxicity, indicating the necessity for I-specific helper T cells for the generation of killer T cells. Finally adult thymectomized, irradiated and bone marrow reconstituted (A X B)F1 mice, transplanted with an irradiated thymus of A origin, generate virus-specific cytotoxic T cells specific for infected A targets but not for B targets; this result formally demonstrates the crucial role of thymic epithelial cells in the differentiation of anti-self-H-2 specificities of T cells.
833 citations
"The lymphoreticular system in trigg..." refers background or methods in this paper
...type H-2 antigens, but not B or C H-2 ant igens (1), however, do genera te killer T cells restricted to the second recipient 's parenta l H-2 C ant igens when tha t...
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...In a follow-up of our own studies and of others (1-3) we analyzed why irradiated, bone marrow reconstituted chimeric mice show such a marked preference of immunologic activity for the reconstituting parental H-2 haplotype....
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...We showed that infected H-2 incompatible or H-2K, I incompatible chimeras do not generate measurable cytotoxic T-cell activity (Zinkernagel et al. 1978....
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...Since, according to our evidence (1), parental stem cells learned to recognize both F~ H-2 haplotypes as self in the F~ thymus, these results suggested that the actual expression of H-2 associated virus-specific cytotoxicity depended on an additional factor....
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...Published methods were used as described in the preceding report (1)....
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TL;DR: The cytotoxic activity of immune thymus-derived lymphocytes (T cells) for 51Cr-labeled fibroblasts or macrophages infected with lymphocytic choriomeningitis (LCM) virus is restricted by the H-2 gene complex as mentioned in this paper.
Abstract: THE cytotoxic activity1,2 of immune thymus-derived lymphocytes (T cells) for 51Cr-labelled fibroblasts, or macrophages infected with lymphocytic choriomeningitis (LCM) virus is restricted by the H-2 gene complex3,4. Specific lysis of LCM-infected monolayer cultures occurs only when targets and overlaying, sensitised T cells share at least one set of H-2 antigenic specificities.
798 citations
"The lymphoreticular system in trigg..." refers result in this paper
...data are in agreement with studies that many viruses infect cells of the LRS (21), and with many examples demonstrating the selective stimulation of FI Tcell activity specific for one parental H-2 type when antigen presenting stimulator cells of this one parent were used (22, 23)....
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TL;DR: Using syngeneic, allogeneic, F1, AND H-2 recombinatn mice, it would seem that there are at least two specificities of tlcm-immune T cells in homozygotes, associated with either H- 2K or H-1D, and four specificities in F1 hybrids.
Abstract: Use of syngeneic, allogeneic, F1, AND H-2 recombinatn mice has shown that animals injected with lymphocytic choriomeningitis (LCM) virus generate T cells which are cytotoxic for H-2K or H-2D compatible, but not H-2 different, virus-infected target cells. Three separate lines of evidence are presented which indicate that these immune T cells are sensitized to "altered-self," the self antigens involved being coded for in the H-2K or H-2d regions. Firstly, cytotoxic activity associated with mutuality at H-2D iy, lysis mediated by immune T cells from F1 or H-2 recombinant mice is specifically inhibited only by presence of unlabeled, virus-infected cells that are H-2 compatible with the targets. Thirdly, LCM-immune F1 and H-2 recombinant T cells inoculated into irradiated, virus-infected recipients proliferate only to kill target cells that are H-2 compatible with both the donor and the recipient. All of these experiments establish that there is a dissociation of T-cell activities between parental haplotypes in F1 mice, and between H-2K and H-2D in recombinants. It would thus seem that there are at least two specificities of tlcm-immune T cells in homozygotes, associated with either H-2K or H-2D, and four specificities in F1 hybrids. The significance of these findings, with respect both to gene duplication and to the marked polymorphism in the H-2 system, is discussed.
607 citations
"The lymphoreticular system in trigg..." refers background in this paper
...The results also indicate that on effector T cells, the anti-self-H-2 specificity is distributed clonally, as has been postulated and shown previously (3, 20)....
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...Results are expressed as a percent of water released and are uncorrected for spontaneous release (20, 21)....
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