PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
 
J Exp Med. 1986 February 1; 163(2): 231–246.
PMCID: PMC2188029

Intrathymic presentation of circulating non-MHC antigens by medullary dendritic cells. An antigen-dependent microenvironment for T cell differentiation

Abstract

We present evidence for intrathymic presentation of soluble circulating antigens in vivo. Our results show that proteins of different molecular weight enter the mouse thymus rapidly after i.v. injection. The intrathymic presence of antigen was assayed by proliferation of cloned antigen-specific T helper cells, which were cocultured with purified thymic stromal cells; stromal cells were isolated and purified as lymphostromal cell complexes, which preexist in vivo. Antigen presentation copurified with non-adherent medullary dendritic cells (DC) (interdigitating cells). I-A- cortical macrophages forming thymocyte rosettes in vivo and I-A+ cortical epithelial cells forming thymic nurse cells (TNC) in vivo did not act as antigen presenting cells (APC) after antigen pulsing in vivo or in vitro. Thymic APC turn over physiologically and are rapidly replaced (within 2-5 wk) after lethal irradiation by donor bone marrow-derived cells. The frequency of thymocyte-DC interactions in vivo strictly correlates with thymic T cell differentiation, and is independent of the immune status of the animal. Fetal thymic APC seem to be secluded from antigen in the maternal circulation. Thymic DC-ROS probably represent the microenvironment where maturing T cells first encounter non-MHC antigens in the context of self-MHC antigens.

Full Text

The Full Text of this article is available as a PDF (1.5M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Haskins K, Kubo R, White J, Pigeon M, Kappler J, Marrack P. The major histocompatibility complex-restricted antigen receptor on T cells. I. Isolation with a monoclonal antibody. J Exp Med. 1983 Apr 1;157(4):1149–1169. [PMC free article] [PubMed]
  • Hedrick SM, Cohen DI, Nielsen EA, Davis MM. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature. 1984 Mar 8;308(5955):149–153. [PubMed]
  • Roehm N, Herron L, Cambier J, DiGuisto D, Haskins K, Kappler J, Marrack P. The major histocompatibility complex-restricted antigen receptor on T cells: distribution on thymus and peripheral T cells. Cell. 1984 Sep;38(2):577–584. [PubMed]
  • Snodgrass HR, Kisielow P, Kiefer M, Steinmetz M, von Boehmer H. Ontogeny of the T-cell antigen receptor within the thymus. Nature. 1985 Feb 14;313(6003):592–595. [PubMed]
  • Scollay RG, Butcher EC, Weissman IL. Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol. 1980 Mar;10(3):210–218. [PubMed]
  • Ceredig R, Glasebrook AL, MacDonald HR. Phenotypic and functional properties of murine thymocytes. I. Precursors of cytolytic T lymphocytes and interleukin 2-producing cells are all contained within a subpopulation of "mature" thymocytes as analyzed by monoclonal antibodies and flow microfluorometry. J Exp Med. 1982 Feb 1;155(2):358–379. [PMC free article] [PubMed]
  • Fink PJ, Gallatin WM, Reichert RA, Butcher EC, Weissman IL. Homing receptor-bearing thymocytes, an immunocompetent cortical subpopulation. Nature. 1985 Jan 17;313(5999):233–235. [PubMed]
  • Fink PJ, Weissman IL, Kaplan HS, Kyewski BA. The immunocompetence of murine stromal cell-associated thymocytes. J Immunol. 1984 May;132(5):2266–2272. [PubMed]
  • Scollay R, Chen WF, Shortman K. The functional capabilities of cells leaving the thymus. J Immunol. 1984 Jan;132(1):25–30. [PubMed]
  • Zinkernagel RM, Callahan GN, Althage A, Cooper S, Klein PA, Klein J. On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition? J Exp Med. 1978 Mar 1;147(3):882–896. [PMC free article] [PubMed]
  • Fink PJ, Bevan MJ. H-2 antigens of the thymus determine lymphocyte specificity. J Exp Med. 1978 Sep 1;148(3):766–775. [PMC free article] [PubMed]
  • Wekerle H, Ketelsen UP, Ernst M. Thymic nurse cells. Lymphoepithelial cell complexes in murine thymuses: morphological and serological characterization. J Exp Med. 1980 Apr 1;151(4):925–944. [PMC free article] [PubMed]
  • Kyewski BA, Rouse RV, Kaplan HS. Thymocyte rosettes: multicellular complexes of lymphocytes and bone marrow-derived stromal cells in the mouse thymus. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5646–5650. [PubMed]
  • Kyewski BA, Kaplan HS. Lymphoepithelial interactions in the mouse thymus: phenotypic and kinetic studies on thymic nurse cells. J Immunol. 1982 May;128(5):2287–2294. [PubMed]
  • Kyewski BA, Travis M, Kaplan HS. Intrathymic lymphopoiesis: stromal cell-associated proliferation of T cells is independent of lymphocyte genotype. J Immunol. 1984 Sep;133(3):1111–1116. [PubMed]
  • Groves ES, Singer A. Role of the H-2 complex in the induction of T cell tolerance to self minor histocompatibility antigens. J Exp Med. 1983 Nov 1;158(5):1483–1497. [PMC free article] [PubMed]
  • Matzinger P, Zamoyska R, Waldmann H. Self tolerance is H-2-restricted. Nature. 1984 Apr 19;308(5961):738–741. [PubMed]
  • Rammensee HG, Bevan MJ. Evidence from in vitro studies that tolerance to self antigens is MHC-restricted. Nature. 1984 Apr 19;308(5961):741–744. [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]
  • Nussenzweig MC, Steinman RM, Witmer MD, Gutchinov B. A monoclonal antibody specific for mouse dendritic cells. Proc Natl Acad Sci U S A. 1982 Jan;79(1):161–165. [PubMed]
  • Kimoto M, Fathman CG. Antigen-reactive T cell clones. I. Transcomplementing hybrid I-A-region gene products function effectively in antigen presentation. J Exp Med. 1980 Oct 1;152(4):759–770. [PMC free article] [PubMed]
  • Shigeta M, Fathman CG. I-region genetic restrictions imposed upon the recognition of KLH by murine T-cell clones. Immunogenetics. 1981;14(5):415–422. [PubMed]
  • Infante AJ, Atassi MZ, Fathman CG. T cell clones reactive with sperm whale myoglobin. Isolation of clones with specificity for individual determinants on myoglobin. J Exp Med. 1981 Nov 1;154(5):1342–1356. [PMC free article] [PubMed]
  • Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med. 1973 May 1;137(5):1142–1162. [PMC free article] [PubMed]
  • Inaba K, Witmer MD, Steinman RM. Clustering of dendritic cells, helper T lymphocytes, and histocompatible B cells during primary antibody responses in vitro. J Exp Med. 1984 Sep 1;160(3):858–876. [PMC free article] [PubMed]
  • Raviola E, Karnovsky MJ. Evidence for a blood-thymus barrier using electron-opaque tracers. J Exp Med. 1972 Sep 1;136(3):466–498. [PMC free article] [PubMed]
  • Steinman RM, Lustig DS, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. 3. Functional properties in vivo. J Exp Med. 1974 Jun 1;139(6):1431–1445. [PMC free article] [PubMed]
  • Brecher G, Ansell JD, Micklem HS, Tjio JH, Cronkite EP. Special proliferative sites are not needed for seeding and proliferation of transfused bone marrow cells in normal syngeneic mice. Proc Natl Acad Sci U S A. 1982 Aug;79(16):5085–5087. [PubMed]
  • Lu CY, Beller DI, Unanue ER. During ontogeny, Ia-bearing accessory cells are found early in the thymus but late in the spleen. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1597–1601. [PubMed]
  • Robinson JH. The ontogeny of antigen-presenting cells in fetal thymus evaluated by MLR stimulation. J Immunol. 1983 Apr;130(4):1592–1595. [PubMed]
  • Van Vliet E, Jenkinson EJ, Kingston R, Owen JJ, Van Ewijk W. Stromal cell types in the developing thymus of the normal and nude mouse embryo. Eur J Immunol. 1985 Jul;15(7):675–681. [PubMed]
  • Beller DI, Unanue ER. IA antigens and antigen-presenting function of thymic macrophages. J Immunol. 1980 Mar;124(3):1433–1440. [PubMed]
  • Papiernik M, Nabarra B, Savino W, Pontoux C, Barbey S. Thymic reticulum in mice. II. Culture and characterization of nonepithelial phagocytic cells of the thymic reticulum: their role in the syngeneic stimulation of thymic medullary lymphocytes. Eur J Immunol. 1983 Feb;13(2):147–155. [PubMed]
  • Kaiserling E, Stein H, Müller-Hermelink HK. Interdigitating reticulum cells in the human thymus. Cell Tissue Res. 1974;155(1):47–55. [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]
  • Duijvestijn AM, Schutte R, Köhler YG, Korn C, Hoefsmit EC. Characterization of the population of phagocytic cells in thymic cell suspensions. A morphological and cytochemical study. Cell Tissue Res. 1983;231(2):313–323. [PubMed]
  • Guillemot FP, Oliver PD, Peault BM, Le Douarin NM. Cells expressing Ia antigens in the avian thymus. J Exp Med. 1984 Dec 1;160(6):1803–1819. [PMC free article] [PubMed]
  • Haynes BF. The human thymic microenvironment. Adv Immunol. 1984;36:87–142. [PubMed]
  • Zinkernagel RM. Selection of restriction specificities of virus-specific cytotoxic T cells in the thymus: no evidence for a crucial role of antigen-presenting cells. J Exp Med. 1982 Dec 1;156(6):1842–1847. [PMC free article] [PubMed]
  • Katz SI, Tamaki K, Sachs DH. Epidermal Langerhans cells are derived from cells originating in bone marrow. Nature. 1979 Nov 15;282(5736):324–326. [PubMed]
  • Steinman RM, Gutchinov B, Witmer MD, Nussenzweig MC. Dendritic cells are the principal stimulators of the primary mixed leukocyte reaction in mice. J Exp Med. 1983 Feb 1;157(2):613–627. [PMC free article] [PubMed]
  • Fink PJ, Bevan MJ, Weissman IL. Thymic cytotoxic T lymphocytes are primed in vivo to minor histocompatibility antigens. J Exp Med. 1984 Feb 1;159(2):436–451. [PMC free article] [PubMed]
  • Kruisbeek AM, Mond JJ, Fowlkes BJ, Carmen JA, Bridges S, Longo DL. Absence of the Lyt-2-,L3T4+ lineage of T cells in mice treated neonatally with anti-I-A correlates with absence of intrathymic I-A-bearing antigen-presenting cell function. J Exp Med. 1985 May 1;161(5):1029–1047. [PMC free article] [PubMed]
  • Nossal GJ. Cellular mechanisms of immunologic tolerance. Annu Rev Immunol. 1983;1:33–62. [PubMed]
  • Ready AR, Jenkinson EJ, Kingston R, Owen JJ. Successful transplantation across major histocompatibility barrier of deoxyguanosine-treated embryonic thymus expressing class II antigens. Nature. 1984 Jul 19;310(5974):231–233. [PubMed]
  • Von Boehmer H, Schubiger K. Thymocytes appear to ignore class I major histocompatibility complex antigens expressed on thymus epithelial cells. Eur J Immunol. 1984 Nov;14(11):1048–1052. [PubMed]

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