Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. Dec 1, 1994; 180(6): 2089–2099.
PMCID: PMC2191800

Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen

Abstract

Transgenic mice expressing a major histocompatibility complex class II- restricted T cell receptor with specificity for a natural self-antigen, the fifth component of complement, were generated to analyze the mechanism of tolerance induction to a blood-borne self-protein. In the absence of C5 protein thymocytes from T cell receptor transgenic mice develop into mature CD4 single positive cells which emigrate into the periphery and mount C5-specific T cell responses upon immunization with C5. In the presence of circulating C5 protein, CD4 single positive thymocytes do not develop. Negative selection occurs late in thymic ontogeny leaving the bulk of CD4+8+ thymocytes unaffected. This phenotype may be due to a delay in contact with self-antigen presentation which, under physiological conditions, is inefficient in the cortex of C5+ mice, and therefore does not affect most immature double positive thymocytes. In contrast, in vitro exposure to C5(-)- presenting dendritic cells or in vivo injection of C5 peptide results in deletion of double positive thymocytes. C5+ transgenic mice are tolerant in vivo, but contain T cells in spleen and lymph nodes that secrete interleukin 2 and interferon gamma in response to C5 activation in vitro. When crossed onto a Rag1-/- background to prevent endogenous T cell receptor rearrangements, these peripheral potentially autoreactive cells do not appear. This indicates that endogenous T cell receptor rearrangements possibly leading to the expression of two receptors might be a prerequisite for their survival and export into the periphery.

Full Text

The Full Text of this article is available as a PDF (1.1M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Kisielow P, Blüthmann H, Staerz UD, Steinmetz M, von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. [PubMed]
  • Pircher H, Bürki K, Lang R, Hengartner H, Zinkernagel RM. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature. 1989 Nov 30;342(6249):559–561. [PubMed]
  • von Boehmer H, Kisielow P. Self-nonself discrimination by T cells. Science. 1990 Jun 15;248(4961):1369–1373. [PubMed]
  • Schönrich G, Kalinke U, Momburg F, Malissen M, Schmitt-Verhulst AM, Malissen B, Hämmerling GJ, Arnold B. Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell. 1991 Apr 19;65(2):293–304. [PubMed]
  • Murphy KM, Heimberger AB, Loh DY. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science. 1990 Dec 21;250(4988):1720–1723. [PubMed]
  • Gervais F, Desforges C, Skamene E. The C5-sufficient A/J congenic mouse strain. Inflammatory response and resistance to Listeria monocytogenes. J Immunol. 1989 Mar 15;142(6):2057–2060. [PubMed]
  • Spanopoulou E, Roman CA, Corcoran LM, Schlissel MS, Silver DP, Nemazee D, Nussenzweig MC, Shinton SA, Hardy RR, Baltimore D. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. Genes Dev. 1994 May 1;8(9):1030–1042. [PubMed]
  • Lin RH, Stockinger B. T cell immunity or tolerance as a consequence of self antigen presentation. Eur J Immunol. 1989 Jan;19(1):105–110. [PubMed]
  • Staerz UD, Rammensee HG, Benedetto JD, Bevan MJ. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J Immunol. 1985 Jun;134(6):3994–4000. [PubMed]
  • Sim GK, Augustin AA. V beta gene polymorphism and a major polyclonal T cell receptor idiotype. Cell. 1985 Aug;42(1):89–92. [PubMed]
  • Mamalaki C, Norton T, Tanaka Y, Townsend AR, Chandler P, Simpson E, Kioussis D. Thymic depletion and peripheral activation of class I major histocompatibility complex-restricted T cells by soluble peptide in T-cell receptor transgenic mice. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11342–11346. [PMC free article] [PubMed]
  • Greaves DR, Wilson FD, Lang G, Kioussis D. Human CD2 3'-flanking sequences confer high-level, T cell-specific, position-independent gene expression in transgenic mice. Cell. 1989 Mar 24;56(6):979–986. [PubMed]
  • Slade SJ, Langhorne J. Production of interferon-gamma during infection of mice with Plasmodium chabaudi chabaudi. Immunobiology. 1989 Oct;179(4-5):353–365. [PubMed]
  • Stockinger B, Hausmann B. Functional recognition of in vivo processed self antigen. Int Immunol. 1994 Feb;6(2):247–254. [PubMed]
  • Lin RH, Stockinger B. Purification of the fifth component of murine complement from ascites fluid. J Immunol Methods. 1988 Nov 25;115(1):127–131. [PubMed]
  • Cobbold SP, Jayasuriya A, Nash A, Prospero TD, Waldmann H. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature. 1984 Dec 6;312(5994):548–551. [PubMed]
  • Pircher H, Rebaï N, Groettrup M, Grégoire C, Speiser DE, Happ MP, Palmer E, Zinkernagel RM, Hengartner H, Malissen B. Preferential positive selection of V alpha 2+ CD8+ T cells in mouse strains expressing both H-2k and T cell receptor V alpha a haplotypes: determination with a V alpha 2-specific monoclonal antibody. Eur J Immunol. 1992 Feb;22(2):399–404. [PubMed]
  • Swat W, Ignatowicz L, Kisielow P. Detection of apoptosis of immature CD4+8+ thymocytes by flow cytometry. J Immunol Methods. 1991 Mar 1;137(1):79–87. [PubMed]
  • Schneider R, Lees RK, Pedrazzini T, Zinkernagel RM, Hengartner H, MacDonald HR. Postnatal disappearance of self-reactive (V beta 6+) cells from the thymus of Mlsa mice. Implications for T cell development and autoimmunity. J Exp Med. 1989 Jun 1;169(6):2149–2158. [PMC free article] [PubMed]
  • Tachibana DK, Rosenberg LT. Fetal synthesis of Hc', a component of mouse complement. J Immunol. 1966 Aug;97(2):213–215. [PubMed]
  • CINADER B, DUBISKI S, WARDLAW AC. DISTRIBUTION, INHERITANCE, AND PROPERTIES OF AN ANTIGEN, MUB1, AND ITS RELATION TO HEMOLYTIC COMPLEMENT. J Exp Med. 1964 Nov 1;120:897–924. [PMC free article] [PubMed]
  • Cairns L, Rosen FS, Borel Y. Mice naturally tolerant to C5 have T cells that suppress the response to this antigen. Eur J Immunol. 1986 Oct;16(10):1277–1282. [PubMed]
  • Jameson SC, Nakajima PB, Brooks JL, Heath W, Kanagawa O, Gascoigne NR. The T cell receptor V alpha 11 gene family. Analysis of allelic sequence polymorphism and demonstration of J alpha region-dependent recognition by allele-specific antibodies. J Immunol. 1991 Nov 1;147(9):3185–3193. [PubMed]
  • Barclay AN, Mayrhofer G. Bone marrow origin of Ia-positive cells in the medulla rat thymus. J Exp Med. 1981 Jun 1;153(6):1666–1671. [PMC free article] [PubMed]
  • Degermann S, Surh CD, Glimcher LH, Sprent J, Lo D. B7 expression on thymic medullary epithelium correlates with epithelium-mediated deletion of V beta 5+ thymocytes. J Immunol. 1994 Apr 1;152(7):3254–3263. [PubMed]
  • Lorenz RG, Allen PM. Thymic cortical epithelial cells lack full capacity for antigen presentation. Nature. 1989 Aug 17;340(6234):557–559. [PubMed]
  • Mizuochi T, Kasai M, Kokuho T, Kakiuchi T, Hirokawa K. Medullary but not cortical thymic epithelial cells present soluble antigens to helper T cells. J Exp Med. 1992 Jun 1;175(6):1601–1605. [PMC free article] [PubMed]
  • Nieuwenhuis P, Stet RJ, Wagenaar JP, Wubbena AS, Kampinga J, Karrenbeld A. The transcapsular route: a new way for (self-) antigens to by-pass the blood-thymus barrier? Immunol Today. 1988 Dec;9(12):372–375. [PubMed]
  • Kyewski BA, Fathman CG, Kaplan HS. Intrathymic presentation of circulating non-major histocompatibility complex antigens. Nature. 1984 Mar 8;308(5955):196–199. [PubMed]
  • Auphan N, Schönrich G, Malissen M, Barad M, Hämmerling G, Arnold B, Malissen B, Schmitt-Verhulst AM. Influence of antigen density on degree of clonal deletion in T cell receptor transgenic mice. Int Immunol. 1992 Apr;4(4):541–547. [PubMed]
  • Malissen M, Trucy J, Jouvin-Marche E, Cazenave PA, Scollay R, Malissen B. Regulation of TCR alpha and beta gene allelic exclusion during T-cell development. Immunol Today. 1992 Aug;13(8):315–322. [PubMed]
  • Heath WR, Miller JF. Expression of two alpha chains on the surface of T cells in T cell receptor transgenic mice. J Exp Med. 1993 Nov 1;178(5):1807–1811. [PMC free article] [PubMed]
  • Padovan E, Casorati G, Dellabona P, Meyer S, Brockhaus M, Lanzavecchia A. Expression of two T cell receptor alpha chains: dual receptor T cells. Science. 1993 Oct 15;262(5132):422–424. [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...