[en] Oxytocin (OT) has been shown to be the dominant peptide of the neurohypophysial family expressed by thymic epithelial and nurse cells (TEC/TNC) in various species. Thymic OT is not secreted but, after translocation of a hybrid neurophysin/MHC class I protein, is integrated within the plasma membrane of TEC, thus allowing its presentation to pre-T cells. In order to further demonstrate that thymic OT behaves like a membrane antigen, we assessed the effect of mAbs to OT on cytokine productions by cultures enriched in human TEC. 75-85% pure TEC cultures were prepared from human thymic fragments. Using immunofluorescence and confocal microscopy, ir-OT, ir-interleukin-1 beta (IL-1 beta), ir-interleukin-6 (IL-6) and ir-leukemia inhibitory factor (LIF) could be detected in these TEC cultures. ir-OT was restricted to TEC, while some ir-IL-6 and ir-LIF were also seen in occasional fibroblasts. In basal conditions, ir-IL-6 and ir-LIF (but not ir-OT and ir-IL-1 beta) were detected in the supernatants of human TEC cultures. MAbs to OT induced a marked increase of ir-IL-6 and ir-LIF secretion in TEC cultures. No significant effect was observed using mAbs against vasopressin, mouse immunoglobulins, or control ascitic fluid controls. These data show that OT is fully processed and recognized by specific mAbs at the outer surface of TEC plasma membrane. They further support that thymic OT behaves as the self-antigen of the neurohypophysial family.
Disciplines :
Immunology & infectious disease
Author, co-author :
Martens, Henri ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Embryologie
Malgrange, Brigitte ; Université de Liège - ULiège > CNCM/ Centre fac. de rech. en neurobiologie cell. et moléc.
Robert, F.
Charlet, C.
De Groote, D.
Heymann, D.
Godard, Alex ; Université de Liège - ULiège > Technologie de l'éducation
Soulillou, J. P.
Moonen, Gustave ; Université de Liège - ULiège > Département des sciences cliniques > Neurologie - Doyen de la Faculté de Médecine
Geenen, Vincent ; Université de Liège - ULiège > Centre d'immunologie
Language :
English
Title :
Cytokine Production by Human Thymic Epithelial Cells: Control by the Immune Recognition of the Neurohypophysial Self-Antigen
Haynes B.F. The human thymic microenvironment. Adv. Immunol. 36:1984;87-142.
Sprent J., Lo D., Gao E.-K., Ron Y. T cell selection in the thymus. Immunol. Rev. 101:1988;173-190.
Muller K.-P., Kyewski B.A. T cell receptor targeting to thymic cortical epithelial cells in vivo induces survival, activation and differentiation of immature thymocytes. Eur. J. Immunol. 23:1993;1661-1670.
Jenkinson E.J., Anderson G., Owen J.J.T. Studies on T cell maturation on defined thymic stromal cell populations in vitro. J. Exp. Med. 176:1992;845-853.
Hugo P., Kappler J.W., Marrack P.C. Positive selection of TcR alpha beta thymocytes: is cortical thymic epithelium an obligatory participant in the presentation of major histocompatibility complex protein? Immunol. Rev. 135:1993;133-155.
Bonomo A., Matzinger P. Thymus epithelium induces tissue-specific tolerance. J. Exp. Med. 177:1993;1153-1164.
Yukmanovic S., Jameson S.C., Bevan M.J. A thymic epithelial cell line induces both positive and negative selection in the thymus. Int. Immunol. 6:1994;239-246.
Geenen V., Martens H., Robert F., De Groote D., Franchimont P. The thymic education of developing T cells in self neuroendocrine principles. J. Endocrinol. Invest. 15:1992;621-629.
Martens H., Goxe B., Geenen V. The thymic repertoire of neuroendocrine self-peptides: Physiological implications in T-cell life and death. Immunol. Today. 17:1996;312-317.
Kelly, P.J., Blalock, J.E., Chrousos, G.P., Yu-Lee, L. and Geenen, V., Neuroendocrine hormones and the immune system. In A. Cuello and B. Collier (Eds.), Pharmacological Sciences: Perpectives for Research and Therapy in the Late 1990s., Birkhäuser, Basel, 1995, pp. 365-372.
Geenen V., Legros J.J., Franchimont P., Baudrihaye M., Defresne M.-P., Boniver J. The neuroendocrine thymus: Coexistence of oxytocin and neurophysin in the human thymus. Science. 232:1986;508-511.
Wiemann M., Ehret G. Subcellular localization of immunoreactive oxytocin within thymic epithelial cells of the male mouse. Cell Tissue Res. 273:1993;79-87.
Elands J., Resink A., de Kloet E.R. Neurohypophysial hormone receptors in the rat thymus, spleen, and lymphocytes. Endocrinology. 126:1989;2703-2710.
Martens H., Robert F., Legros J.J., Geenen V., Franchimont P. Expression of functional neurohypophysial peptide receptors by murine immature and cytotoxic T cell lines. Prog. NeuroEndocrin-Immunol. 5:1992;31-39.
Geenen V., Robert F., Martens H., Benhida A., Degiovanni G., Defresne M.-P., Boniver J., Legros J.J., Martial J., Franchimont P. Biosynthesis and paracrine/cryptocrine actions of "self" neurohypophysial-related peptides in the thymus. Mol. Cell. Endocrinol. 76:1991;C27-C31.
Geenen V., Legros J.-J., Franchimont P., Defresne M.-P., Boniver J., Ivell R., Richter D. The thymus as a neuroendocrine organ. synthesis of vasopressin and oxytocin in human thymic epithelium. Ann. NY Acad. Sci. 496:1987;56-66.
Geenen, V., Vandersmissen, E., Martens, H., Goxe, B., Kecha, O., Legros, J.-J., Lefebvre, P.J., Benhida, A. Rentier-Delrue, F. and Martial, J.A., Cellular and molecular aspects of thymic T-cell education to neurohypophysial principles. In T. Saito, K. Kurokawa and S. Yoshida (Eds.), Neurohypophysis. Recent progress of vasopressin and oxytocin research. Proceedings of the First Joint World Congress of Neurohypophysis and Vasopressin, Excerpta Medica International Congress Series 1098, Elsevier, Amsterdam, 1995, pp. 309-319.
Geenen V., Vandersmissen E., Cormann-Goffin N., Martens H., Legros J.J., Degiovanni G., Benhida A., Martial J., Franchimont P. Membrane translocation and relationship with MHC class I of a human thymic neurophysin-like protein. Thymus. 22:1993;55-66.
Gainer, H. and Wray, S., Cellular and molecular biology of oxytocin and vasopressin. In E. Knobil and J.D. Neill (Eds.), The Physiology of Reproduction, 2nd Edn., Raven Press, New York, 1993, pp. 1099-1129.
Geenen V., Kroemer G. The multiple ways to cellular immune tolerance. Immunol. Today. 14:1993;573-575.
Le P.T., Tuck D.T., Dinarello C.A., Haynes B.F., Singer K.H. Human thymic epithelial cells produce interleukin-1. J. Immunol. 138:1987;2520-2526.
Le P.T., Lazorick S., Whichard L.P., Yang Y.C., Clarck S.C., Haynes B.F., Singer K.H. Human thymic epothelial cells produce IL-6, granulocyte-monocyte-CSF, and leukemia inhibitory factor. J. Immunol. 145:1990;3310-3315.
Robert F., Geenen V., Schoenen J., Burgeon E., De Groote D., Defresne M.-P., Legros J.J., Franchimont P. Co-localization of immunoreactive oxytocin, vasopressin and interleukin-1 in human thymic epithelial neuroendocrine cells. Brain Behav. Immun. 5:1991;102-115.
Burgeon E., Chapleur M., Schoenen J., Remichius D., Legros J.J., Geenen V., Robert F. Monoclonal antibodies to oxytocin: Production and characterization. J. Neuroimmunol. 31:1991;235-244.
Robert F.R., Leon-Henri B.P., Chapleur-Chateau M.M., Girr M.N., Burlet A.J. Comparison of three immunoassays in the screening and characterization of monoclonal antibodies against arginine-vasopressin. J. Neuroimmunol. 9:1985;205-220.
Coupley L., Berrada L., Gascan H., Godard A., Praloran V. High titre antibodies obtained by intralymphnode immunization with low amounts of antigen. Cytokine. 5:1993;564-569.
Gilbert S.F., Migeon B.R. D-Valine as a selective agent for normal human and rodent epithelial cells in culture. Cell. 5:1975;11-17.
Small M., Barr-Nea L., Aronson M. Culture of thymic epithelial cells from mice and age-related studies on the growing cells. Eur. J. Immunol. 14:1984;936-942.
Christensson B., Biberfeld P., Grafstrom R., Matell G. In vitro culture of human thymic epithelial cells in serum-free media. APMIS. 97:1989;926-934.
De Groote D., Zangerlé P.F., Gevaert Y., Fassotte M.F., Beguin Y., Noizat-Pirenne F., Pirenne J., Gathy R., Lopez M., Dehart I., Igot D., Baudrihaye M., Delacroix D., Franchimont P. Direct stimulation of cytokines (IL-1β, TNFα, IL-6, IL-2, IFNγ and GM-CSF) in whole blood: I. Comparison with isolated PBMC stimulation Cytokine. 4:1992;239-248.
De Groote D., Fauchet F., Jadoul M., Dehart I., Gevaert Y., Lopez M., Gathy R., Franssen J.D., Radoux D., Franchimont P., Soulillou J.P., Jacques Y., Godard A. An Elisa for the measurements of human leukemia inhibitory factor in biological fluids and culture supernatants. J. Immunol. Methods. 167:1994;253-261.
Andersen A., Pedersen H., Bendtzen K., Ropke C. Effects of growth factors on cytokine production in serum-free cultures of human thymic epithelial cells. Scand. J. Immunol. 38:1993;233-238.
Le P.T., Lazorick S., Whichard L.P., Haynes B.F., Singer K.H. Regulation of cytokine production in the human thymus: epidermal growth factor and transforming growth factor-α regulate mRNA levels of interleukin-1α (IL-1α), IL-1β and IL-6 in human thymic epithelial cells at a post-transcriptional level. J. Exp. Med. 174:1991;1147-1157.
Colic M., Pejnovic N., Katanranovski M., Stojanovic N., Terzic T., Dujic A. Rat thymic epithelial cells in culture constitutively secrete IL-1 and IL-6. Int. Immunol. 3:1991;1165-1174.
Eshel I., Savion N., Shoham J. Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium. II. Cytokines activities in murine thymic epithelial and mesenchymal cell culture supernatants J. Immunol. 144:1990;1563-1570.
Meilin A., Shoham J., Sharabi Y. Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium. IV. Cytokines secreted by human thymic epithelial cells in culture and theiractivities on murine thymocytes and bone marrow cells Immunology. 77:1992;208-213.
Robert F., Martens H., Cormann N., Benhida A., Schoenen J., Geenen V. The recognition of hypothalamo-neurohypophysial functions by developing T cells. Dev. Immunol. 2:1992;131-140.
Ericsson A., Genen V., Robert F., Legros J.J., Vrindts-Gevaert Y., Franchimont P., Brene S., Persson H. Expression of preprotachykinin A and neuropeptide Y mRNA in the thymus. Mol. Endocrinol. 4:1990;1211-1218.
Geenen V., Achour I., Robert F., Vandersmissen E., Sodoyez J.C., Defresne M.-P., Boniver J., Lefebvre P.J., Franchimont P. Evidence that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin superfamily. Thymus. 21:1993;115-127.
Kooijman R., van Buul-Offers S.C., Scholtens L.E., Schuurman H.J., Van den Brande L.J., Zegers B.J.M. T cell development in insulin-like growth factor-II transgenic mice. J. Immunol. 154:1995;5736-5745.