Elsevier

Human Immunology

Volume 52, Issue 2, February 1997, Pages 82-94
Human Immunology

Split tolerance to the MHC class I molecule H-2Dd in animals transgenic for its soluble analog

https://doi.org/10.1016/S0198-8859(96)00287-XGet rights and content

Abstract

To determine whether the function of MHC molecules in tolerance and education is related to cell surface expression, we have produced two strains of transgenic mice in the C57B1/6 background that express soluble analogs of the H-2Dd class I protein. The transgenes were stably integrated and genetically transmitted in a Mendelian fashion. Messenger RNA for the hybrid genes was detected in all tissues analyzed in a class I-like pattern of expression, with the highest levels in lymphoid tissues. All mice bearing the transgenes expressed relatively high levels (0.1 mg/ml) of the encoded protein in their serum as assessed by Western blotting and enzymelinked immunosorbent assay (ELISA). Gel filtration chromatography showed that the soluble H-2Dd protein exists as a heterodimer with β2-microglobulin and as higher order multimers in serum. Lymphoid cells from the transgenic mice showed no cell surface expression of the soluble class I protein in indirect immunofluorescence assays. Splenocytes from two independently derived transgenic lines generated primary cytotoxic and proliferative responses directed against membrane H-2Dd antigens. Mice of both strains rejected tail skin from donors that differed from the B6 background at the H-2Dd locus only, but with delayed kinetics compared to nontransgenic littermate controls. Mice expressing the transgenic protein on immunization did not produce antibodies that recognized soluble H-2D in ELISA, whereas B6 mice generated strong antibody responses to challenge with splenocytes bearing cell surface H-2Dd . Thus, transgenic mice expressing soluble H-2D were partially tolerant to stimulation by membrane-bound H-2D . As with the activation of T-cells, the induction and maintenance of immunologie tolerance apparently displayed different requirements depending upon the T-cell subpopulation involved.

References (67)

  • ParnesJR et al.

    Structure of wild-type and mutant mouse beta 2-microglobulin genes

    Cell

    (1982)
  • GermainRN

    MHC-dependent antigen processing and peptide presentation: Providing ligands for T lymphocyte activation

    Cell

    (1994)
  • SchonrichG et al.

    Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction

    Cell

    (1991)
  • SchneckJ et al.

    Inhibition of an allospecific T cell hybridoma by soluble class I proteins and peptides: estimation of the affinity of a T cell receptor for MHC

    Cell

    (1989)
  • von BoehmerH

    Developmental biology of T cells in T cell-receptor transgenic mice

    Annu Rev Immunol

    (1990)
  • HugoP et al.

    Positive selection of TcR alpha beta thymocytes: Is cortical thymic epithelium an obligatory participant in the presentation of major histocompatibility complex protein?

    Immunol Rev

    (1993)
  • BevanMJ et al.

    Selecting the T cell receptor repertoire

    Science

    (1994)
  • AbastadoJP et al.

    Dimerization of soluble major histocompatibility complex-peptide complexes is sufficient for activation of T cell hybridoma and induction of unresponsiveness

    J Exp Med

    (1995)
  • FerberI et al.

    Levels of peripheral T cell tolerance induced by different doses of tolerogen

    Science

    (1994)
  • SebzdaE et al.

    Positive and negative thymocyte selection induced by different concentrations of a single peptide

    Science

    (1994)
  • SpainLM et al.

    A peptide antigen antagonist prevents the differentiation of T cell receptor transgenic thymocytes

    J Immunol

    (1994)
  • BretscherPA et al.

    Minimal model for the mechanism of antibody induction and paralysis by antigen

    Nature

    (1968)
  • JenkinsMK et al.

    T-cell unresponsiveness in vivo and in vitro: Fine specificity of induction and molecular characterization of the unresponsive state

    Immunol Rev

    (1987)
  • HardingFA et al.

    CD28-B7 interactions allow the induction of CD8 + cytotoxic T lymphocytes in the absence of exogenous help

    J Exp Med

    (1993)
  • GimmiCD et al.

    Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation

  • Van SeventerGA et al.

    Costimulation of T cell receptor/CD3-mediated activation of resting human CD4+ T cells by leukocyte function-associated antigen-1 ligand intercellular cell adhesion molecule-1 involves prolonged inositol phospholipid hydrolysis and sustained increase of intracellular Ca2+ levels

    J Immunol

    (1992)
  • ZuckermanLA et al.

    Identification of a unique costimulatory activity for murine T helper 1 T cell clones

    J Immunol

    (1995)
  • ClarkEA et al.

    How B and T cells talk to each other

    Nature

    (1994)
  • StrasserA et al.

    Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease

  • WebbCF et al.

    Immunoglobulin receptor signaling depends on the carboxyl terminus but not the heavy-chain class

  • GoodnowCC et al.

    Induction of self-tolerance in mature peripheral B lymphocytes

    Nature

    (1989)
  • MannDW et al.

    Cytotoxic T lymphocytes from mice with soluble class I Q10 molecules in their serum are not tolerant to membrane-bound Q10

    J Immunol

    (1987)
  • ArnoldB et al.

    Alloreactive immune responses of transgenic mice expressing a foreign transplantation antigen in a soluble form

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