Involvement of Insulin-Like Growth Factors in Early T Cell Development: A Study Using Fetal Thymic Organ Cultures

[en] The expression of insulin-like growth factor (IGF) and IGF receptor genes was investigated by RT-PCR during ontogeny of the murine thymus. IGF-1, IGF-1R, M6P/IGF-2R genes are expressed in the thymus both in fetal and postnatal life, whereas IGF-2 messenger RNAs (mRNAs) decline after birth but are still detectable on the seventh week. By in situ hybridization, IGF-2 transcripts were located in the outer cortex and medulla of the postnatal thymus, and on the whole surface ofthe epithelial-like network in the fetal thymus. The effects of anti-IGFs and IGF-receptors neutralizing Abs on the generation of pre-T cell subpopulations were then investigated using fetal thymic organ cultures (FTOC). FTOC treatment with an anti-IGF-2 mAb, an anti-IGF-1R mAb, or an anti-M6P/IGF-2R polyclonal Ab induced a blockade of T cell differentiation at the CD4-CD8- stage, as shown by a significant increase in the percentage of CD4-CD8- cells and a decrease in the percentage of CD4+CD8+ cells. Moreover, anti-IGF-2 Ab treatment induced an increase in CD8+ cells suggesting that thymic IGF-2 might have a role in determining differentiation into the CD4 or CD8 lineage. Anti-IGF-1 Ab treatment decreased the proportion in CD4-CD8- cells and increased the frequency in CD4+CD8+. FTOC treatment with anti-(pro)insulin did not exert any significant effect on T cell development. These data indicate that the intrathymic IGF-mediated signaling plays an active role in the early steps of T cell differentiation during fetal development.

Disciplines :

Endocrinology, metabolism & nutrition
Immunology & infectious disease

Author, co-author :

Kecha, O.

Brilot, F.

Martens, Henri ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Embryologie

Franchimont, N.

Renard, Cécile ; Centre Hospitalier Universitaire de Liège - CHU > Rééducation de la parole

Greimers, Roland ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques

Defresne, Marie-Paule ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie - Cytologie

Winkler, Rose ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques

Geenen, Vincent ; Université de Liège - ULiège > Centre d'immunologie

Language :

English

Title :

Involvement of Insulin-Like Growth Factors in Early T Cell Development: A Study Using Fetal Thymic Organ Cultures

Publication date :

March 2000

Journal title :

Endocrinology

ISSN :

0013-7227

eISSN :

1945-7170

Publisher :

The Endocrine Society, United States - Maryland

Volume :

141

Issue :

Pages :

1209-17

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 18 October 2009

Statistics

Number of views

127 (14 by ULiège)

Number of downloads

282 (11 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Herold K.C., Quintans J. (1995) Immunological mechanisms causing autoimmume endocrine diseases. Endocrinology, ed. 3 , DeGroot LJ, Besser M, Burger HG, Jameson JL, Loriaux DL, Marshall JC, Odell WD, Polts Jr JT, Rubenstein AH, Cahill Jr GF, Martini L, Nelson DH (eds). Philadelphia, Saunders; 3:2990-3012.
Geenen V., Kroemer G. (1993) Multiple ways to cellular immune tolerance. Immunol Today 14:573-575.
Shortman K., Wu L. (1996) Early T lymphocyte progenitors. Annu Rev Immumol 14:29-47.
Von Boehmer H. (1992) Thymic selection: A matter of life and death. Immumol Today 13:454-458.
Boyd R.L., Tucek C.L., Godfrey D.I., Izon D.J., Wilson T.J., Davidson N.J., Bean A.G.D., Ladyman H.M., Ritter M.A., Hugo P. (1993) The thymic microenvironment. Immunol Today 14:445-459.
Martens H., Goxe B., Geenen V. (1996) The thymic repertoire of neuroendocrine self-antigens: Physiological implications in T-cell life and death. Immunol Today 17:312-317.
Geenen V., Kecha O., Martens H. (1998) Thymic expression of neuroendocrine self-peptide precursors: Role in T cell survival and self-tolerance. J Neuroendocrinol 10:811-822.
Martens H., Malgrange B., Robert F., Charlet C., De Groote D., Heymann D., Godard A., Soulillou J.P., Moonen G., Geenen V. (1996) Cytokine production by human thymic epithelial cells: Control by the immune recognition of the neurohypophysial self-antigen. Regul Pept 67:39-45.
Vanneste Y., Ntodou Thome A., Vandersmissen E., Charlet C., Franchimont D., Martens H., Lhiaubet A.M., Schimpff R.M., Rostène W., Geenen V. (1997) Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibfiity complex class I molecules. J Neuroimmunol 76:161-166.
Gjerset R.A., Yeargin J., Volkman S.K., Vila V., Arya J., Haas M. (1990) Insulin-like growth factor-I supports proliferation of autocrine thymic lymphoma cells with a pre-T cell phenotype. J Immunol 145:3497-3501.
Binz K., Joller P., Froesch P., Binz H., Zapf J., Froesch E.R. (1990) Repopulation of the atrophied thymus in diabetic rats by insulin-like growth factor 1. Proc Natl Acad Sci USA 87:3690-3694.
Li Y.M., Brunke D.L., Dantzer R., Kelley K.W. (1992) Pituitary epithelial cell implants reverse the accumulation of CD4-CD8-lymphocytes in thymus glands of aged rats. Endocrinology 130:2703-2709.
Kelley K.W., Arkins S., Li Y.M. (1992) Growth hormone, prolactin, and insulin-like growth factors: New jobs for old players. Brain Behav Immun 6:317-326.
Murphy W.J., Durum S.K., Longo D.L. (1992) Role of neuroendocrine hormones in murine T cell development: Growth hormone exerts thymopoietic effects in vivo. J Immunol 149:3851-3857.
Clarke R. (1997) The somatogenic hormones and insulin-like growth factor-1: Stimulators of lymphopoiesis and immune function. Endocr Rev 18:157-179.
Humbel R.E. (1990) Insulin-like growth factors I and II. Eur J Biochem 190:445-462.
LeRoith D., Werner H., Beitner-Johnson D., Roberts C.T. Jr. (1995) Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16:143-163.
Morgan D.O., Edman J.C., Standring D.N., Fried V.A., Smith M.C., Roth R.A., Rutter W.J. (1987) Insulin-like growth factor II receptor as a multifunctional binding protein. Nature 329:301-307.
Morrione A., Valentinis B., Xu S.Q., Yumet G., Louvi A., Efstratiadis A., Baserga R. (1997) Insulin-like growth factor II stimulates cell proliferation through the insulin receptor. Proc Natl Acad Sci USA 94:3777-3782.
Stewart C.E., Rotwein P. (1996) Growth, differentiation, and survival: Multiple physiological functions for insulin-like growth factors. Physiol Rev 76:1005-1026.
Dennis P.A., Rifkin D.B. (1991) Cellular activation of latent transforming growth factor beta requires binding to the cation-independent marmose 6-phosphate/insulin-like growth factor type II receptor. Proc Natl Acad Sci USA 88:580-584.
Kang J.X., Li Y., Leaf A. (1997) Mannose-6-phosphate/insulin-like growth factor-II receptor is a receptor for retinoic acid. Proc Natl Acad Sci USA 94:13671-13676.
Jones J.L., Clemmons D.R. (1995) Insulin-like growth factors and their binding proteins. Endocr Rev 16:3-34.
Kelley K.M., Oh Y., Gargosky S.E., Gucev Z., Matsumoto T., Hwa V., Ng L., Simpson D.M., Rosenfeld R.G. (1996) Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. Int J Biochem Cell Biol 28:619-637.
Geenen V., Achour I., Robert F., Vandersmissen E., Sodoyez J.C., Defresne M.P., Boniver J., Lefèbvre P.J., Franchimont P. (1993) Evidence that insulin-like growth factor 2 (IGF-2) is the dominant thymic member of the insulin superfamily. Thymus 21:115-127.
Kecha O., Martens H., Franchimont N., Achour I., Hazèe-Hagelstein M.T., Renard-Charier C., Geenen V., Winkler R. (1999) Characterization of the insulin-like growth factor axis in the human thymus. J Neuroendocrinol 11:435-440.
Arkins S., Rebeiz N., Biragyn A., Reese D.L., Kelley K.W. (1993) Murine macrophages express abundant insulin-like growth factor-I class I Ea and Eb transcripts. Endocrinology 133:2334-2343.
Verland S., Gammeltoft S. (1989) Functional receptors for insulin-like growth factors I and II in rat thymocytes and mouse thymoma cells. Mol Cell Endocrinol 67:207-216.
Kooijman R., Scholtens L.E., Rijkers G.T., Zegers B.J.M. (1995) Type 1 insulin-like growth factor receptor expression in different developmental stages of human thymocytes. J Endocrinol 147:203-209.
Goxe B., Martens H., Vandersmissen E., Achour I., Kecha O., Geenen V. (1995) Interactions entre les cellules T et la famille insulinique: Ètude du rècepteur de l'IGF-II. Ann Endocrinol (Paris) , Abstract; 56:399.
Clark R., Strasser J., McCabe S., Robbins K., Jardieu P. (1993) Insulin-like growth factor-1 stimulation of lymphopoiesis. J Clin Invest 92:540-548.
Hinton P.S., Peterson C.A., Dahly E.M., Ney D.M. (1998) IGF-I alters lymphocyte survival and regeneration in thymus and spleen after dexamethasone treatment. Am J Physiol 274.
Kooijman R., Van Buul-Offers S.C., Scholtens L.E., Schuurman H.J., Van den Brande L.J., Zegers B.J. (1995) T cell development in insulin-like growth factor-H transgenic mice. J Immunol 154:5736-5745.
Plum J., De Smedt M., Leclercq G., Vandekerckhove B. (1995) Influence of TGF-β on murine thymocyte development in fetal thymus organ culture. J Immunol 154:5789-5798.
Hill P.A., Reynolds J.J., Meikle M.C. (1995) Osteoblasts mediate insulin-like growth factor-I and-II stimulation of osteoclast formation and function. Endocrinology 136:124-131.
Leung K., Rajkovic I.A., Peters E., Markus I., Van Wyk J.J., Ho K.K. (1996) Insulin-like growth factor I and insulin down regulate growth hormone (GH) receptors in rat osteoblasts: Evidence for a peripheral feedback loop regulating GH action. Endocrinology 137:2694-3270.
Li Y.M., Schacher D.H., Liu Q., Arkins S., Rebeiz N., McCusker R.H. Jr., Dantzer R., Kelley K.W. (1997) Regulation of myeloid growth and differentiation by the insulin-like growth factor I receptor. Endocrinology 138:362-368.
MacDonald R.G., Pfeffer S.R., Coussens L., Tepper M.A., Brocklebank C.M., Mole J.E., Anderson J.K., Chen E., Czech M.P., Ullrich A. (1988) A single receptor binds both insulin-like growth factor II and mannose-6-phosphate. Science 239:1134-1137.
Stempien M.M., Fong N.M., Rall L.B., Bell G.I. (1986) Sequence of a placental cDNA encoding the mouse insulin-like growth factor II precursor. DNA 5:357-361.
Clawson T.F., Lee W.H., Yoder M.C. (1996) Differential expression of insulin-like growth factor binding proteins in murine hematopoietic stromal cell lines. Mol Cell Endocrinol 120:59-66.
Rho O., Bol D.K., You J., Beltran L., Rupp T., DiGiovanni J. (1996) Altered expression of insulin-llke growth factor I and its receptor during multistage carcinogenesis in mouse skin. Mol Carcinog 17:62-69.
Szabo P.E., Mann J.R. (1995) Biallelic expression of imprinted genes in the mouse germ line: Implications for erasure, establishment, and mechanisms of genomic imprinting. Genes Dev 9:1857-1868.
Bell G.I., Stempien M.M., Fong N.M., Rall L.B. (1986) Sequences of liver cDNAs encoding two different mouse insulin-like growth factor I precursors. Nucleic Acids Res 14:7873-7882.
Gangji V., Rydziel S., Gabbitas B., Canalis E. (1998) Insulin-like growth factor II promoter expression in cultured rodent osteoblasts and adult rat bone. Endocrinology 139:2287-2292.
Kooijman R., Van Buul-Offers S.C., Scholtens L.E., Reijnen-Gtesnigt R.G., Zegers B.J. (1997) T and B cell development in pituitary deficient insulin-like growth factor-II transgerdc dwarf mice. J Endocrinol 155:5736-5745.
Jolicoeur C., Hanahan D., Smith K.M. (1994) T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in the thymus. Proc Natl Acad Sci USA 91:6707-6711.
Throsby M., Homo-Delarche F., Chevenne D., Goya R., Dardenne M., Pleau J.M. (1998) Pancreatic hormone expression in the murine thymus: Localization in dendritic cells and macrophages. Endocrinology 139:2399-2406.
Minshall C., Arkins S., Freund G.G., Kelley K.W. (1996) Requirement for phosphatidylinositol 3′-kinase to protect hemopoletic progenitors against apoptosis depends upon the extracellular survival factor. J Immunol 156:939-947.
Liu Q., Schacher D., Hurth C., Freund G.G., Dantzer R., Kelley K.W. (1997) Activation of phosphatidylinositol 3′-kinase by insulin-like growth factor-I rescues promyeloid cells from apoptosis and permits their differentiation into granulocytes. J Immunol 159:829-837.
Pàrrizas M., Saltiel A.R., LeRoith D. (1997) Insulin like growth factor 1 inhibits apoptosis using the phosphatidylhnositol 3′-kinase and mitogen-activated prorein kinase pathways. J Biol Chem 272:154-161.
Napolitano M., Bellavia D., Maroder M., Farina M., Alessandra V., Frati L., Gulino A., Screpanti A. (1997) Modulation of cytokine gene expression by thymic lympho-stromal cell to cell interaction: Effect of retinoic add. Thymus 24:247-258.
Yagi J., Uchida T., Kuroda K., Uchiyama T. (1997) Influence of retinoic acid on the differentiation pathway of T cells in the thymus. Cell Immunol 181:153-162.