The Thymic Insulin-like Growth Factor Axis: Involvement in Physiology and Disease

Abstract

A repertoire of neuroendocrine-related genes is transcribed in the non-lymphoid compartment of the thymus, transposing the dual physiological role of this organ at the molecular level in T-cell development towards the establishment of central T-cell self-tolerance. The ”neuroendocrine self” has been defined as a series of antigen sequences processed from precursors predominantly expressed in the thymus and first encountered by differentiating T-lymphocytes in their early life. All the members of the insulin gene family are expressed in the thymus according to a precise hierarchy and cellular topography, whereby IGF-II (epithelium of the subcapsular cortex and medulla) exceeds IGF-I (macrophages), which in turn far exceeds INS (rare subsets of medullary epithelial cells). This hierarchy in the degree of their respective thymic expression explains why IGF-II is more tolerated than IGF-I, and much more so than insulin. Evidence has been found for significant regulatory/tolerogenic properties in the IGF-II B:11 - 25 sequence after analysis of the cytokine secretion profile in peripheral blood mononuclear cells isolated from ten DQ8+ type 1 diabetic adolescents. In the thymus, IGF ligands and receptors also intervene in the control of T-cell proliferation and differentiation. Here, we also discuss how a disturbance in the intrathymic IGF-mediated signaling could contribute to the pathogenesis of T-cell leukemia.

Thymus epithelium - Self-tolerance - Autoimmunity - Type 1 diabetes - T-cell leukemia - Tolerogenic vaccine

References

• 1 Benoist C, Mathis D. T-lymphocyte Differentiation and Biology. In: Paul WE (ed) Fundamental Immunology 4^th Edition. Philadelphia; Lippincott-Raven 1999: 367-409
• 2 Mason D, Powrie F. Control of immune pathology by regulatory T-cells.  Curr Opin Immunol. 1998;  10 649-655
• 3 Sakagushi S. Policing the regulators.  Nat Immunol. 2001;  2 283-284
• 4 Kamradt T, Mitchison N A. Tolerance and autoimmunity.  N Engl J Med. 2001;  344 655-664
• 5 Bennett A R, Farley A, Blair N F, Gordon J, Sharp L, Blackburn C C. Identification and characterization of thymic epithelial progenitor cells.  Immunity. 2002;  16 803-814
• 6 Girr J, Malin M, Holländer G A, Boyd R. Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells.  Nat Immunol. 2002;  3 635-642
• 7 Penninger J, Rieker T, Romani N, Klima J, Salvenmoser W, Dietrich H, Stössel H, Wick G. Ultrastructural analysis of thymic nurse cell epithelium.  Eur J Immunol. 1993;  24 222-229
• 8 Lorenz R G, Allen P M. Thymic cortical epithelial cells can present self-antigens in vivo. .  Nature. 1989;  337 560-562
• 9 Ashton-Rickardt P G, Tonegawa S. A differential-affinity model for T-cell selection.  Immunol Today. 1994;  15 362-366
• 10 Geenen V, Robert F, Martens H, De Groote D, Franchimont P. The thymic education of developing T-cells in self neuroendocrine principles.  J Endocr Invest. 1992;  15 621-629
• 11 Robert F, Martens H, Cormann N, Benhida A, Schoenen J, Geenen V. The recognition of hypothalamo-neurohypophysial functions by developing T-cells.  Dev Immunol. 1992;  2 131-140
• 12 Jolicoeur C, Hanahan D, Smith K M. T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous genes in the thymus.  Proc Natl Acad Sci USA. 1994;  91 6707-6711
• 13 Hanahan D. Peripheral-antigen-expressing cells in thymus medulla: factors in self-tolerance and autoimmunity.  Curr Opin Immunol. 1998;  10 656-662
• 14 Savino W, Dardenne M. Neuroendocrine control of thymus physiology.  Endocr Rev. 2000;  21 412-443
• 15 Kyewski B, Derbinski J, Gotter J, Klein L. Promiscuous gene expression and central T-cell tolerance: more than meets the eye.  Trends Immunol. 2002;  23 364-371
• 16 Geenen V, Legros J J, Franchimont P, Baudrihaye M, Defresne M P, Boniver J. The thymus as a neuroendocrine organ: coexistence of oxytocin and neurophysin in the human thymus.  Science. 1986;  232 508-511
• 17 Ericsson A, Geenen V, Robert F, Legros J J, Vrindts-Gevaert Y, Franchimont P, Brene S, Persson H. Expression of preprotachykinin-A and neuropeptide-Y messenger RNA in the thymus.  Mol Endocr. 1990;  4 1211-1218
• 18 Funder J W. Paracrine, cryptocrine, acrocrine.  Mol Cell Endocrinol. 1990;  70 C21-C24
• 19 Geenen V, Goxe B, Martens H, Vandersmissen E, Vanneste Y, Achour I, Kecha O, Lefebvre P J. Cryptocrine signaling in the thymus network and T-cell education to neuroendocrine self-antigens.  J Mol Med. 1995;  73 449-455
• 20 Geenen V, Vandersmissen E, Martens H, Cormann-Goffin N, Degiovanni G, Legros J J, Benhida A, Martial J, Franchimont P. Membrane translocation and association with MHC class I of a human thymic neurophysin-like protein.  Thymus. 1993;  22 55-66
• 21 Vanneste Y, Ntodou-Thome A, Vandersmissen E, Charlet C, Franchimont D, Martens H, Schimpff R M, Rostene W, Geenen V. Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibility complex class I molecules.  J Neuroimmunol. 1997;  76 161-166
• 22 Geenen V, Brilot F, Hansenne I, Charlet C, Martens H. Thymus and T Cells. In: Adelman G, Smith BH (eds) Encyclopedia of Neuroscience 3^rd Edition. New York; Elsevier 2003: in press
• 23 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 (IGF-II) is the dominant thymic peptide of the insulin superfamily.  Thymus. 1993;  21 115-127
• 24 van Buul-Offers S C, de Haan K, Reijnen-Gresnigt M G, Meinsma D, Jansen M, Oei S L, Bonte E J, Sussenbach J S, Van den Brande J L. Overexpression of human insulin-like growth factor-II in transgenic mice causes increased growth of the thymus.   J Endocrinol. 1995;  144 491-502
• 25 Van der Ven L TM, Roholl P JM, Reijnen-Gresnigt M G, Bloemen R J, van Buul-Offers S C. Expression of insulin-like growth factor II (IGF-II) and histological changes in the thymus and spleen of transgenic mice overexpressing IGF-II.  Histochem Cell Biol. 1997;  107 193-203
• 26 Kooijman R, van Buul-Offers S C, Scholtens L E, Schuurman H J, van den Brande L J, Zegers B JM. T-cell development in insulin-like growth factor-II transgenic mice.  J Immunol. 1995;  154 5736-5745
• 27 Kecha O, Martens H, Franchimont N, Achour I, Hazée-Hagelstein M T, Charlet-Renard C, Geenen V, Winkler R. Characterization of the insulin-like growth factor axis in the human thymus.  J Neuroendocrinol. 1999;  11 435-440
• 28 Montecino-Rodriguez E, Clark R, Dorshkind K. Effects of insulin-like growth factor administration and bone marrow transplantation on thymopoiesis in aged mice.  Endocrinology. 1998;  139 4120-4126
• 29 Kecha O, Brilot F, Martens H, Franchimont N, Renard C, Greimers R, Defresne M P, Winkler R, Geenen V. Involvement of insulin-like growth factors in early T-cell development: a study using fetal thymic organ cultures.  Endocrinology. 2000;  141 1209-1217
• 30 Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.  Nat Immunol. 2001;  2 1032-1039
• 31 Egwuagu C E, Charukamnoetkanok P, Gery I. Thymic expression of autoantigens correlates with resistance to autoimmune disease.  J Immunol. 1997;  159 3109-3112
• 32 Sospedra M, Ferrer-Francesch X, Dominguez O, Juan M, Foz-Sala M, Pujol-Borrell R. Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanism in tolerance towards peripheral antigens.  J Immunol. 1998;  161 5918-5929
• 33 Vafiadis P, Bennett S T, Todd J A, Nadeau J, Grabs R, Goodyer C G, Wickramasinghe S, Colle E, Polychronakos C. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus.  Nat Genet. 1997;  15 289-292
• 34 Pugliese A, Zeller M, Fernandez A Jr, Zalcberg L J, Bartlett R J, Ricordi C, Pietropaolo M, Eisenbarth G S, Bennett S T, Patel D D. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes.  Nat Genet. 1997;  15 293-297
• 35 Zapf J, Walter H, Froesch E R. Radioimmunological determination of insulin-like growth factors I and II in normal subjects and in patients with growth disorders and extrapancreatic tumor hypoglycemia.  J Clin Invest. 1981;  68 1321-1330
• 36 Naquet P, Ellis J, Tibensky D, Kenshole A, Singh B, Hodges R, Delovitch T L. T-cell autoreactivity to insulin in diabetic and related non-diabetic individuals.  J Immunol. 1988;  140 2569-2578
• 37 Like A A, Kislaukis E, Williams R M, Rossini A A. Neonatal thymectomy prevents spontaneous diabetes mellitus in the BB:W rat.  Science. 1982;  216 644-646
• 38 Georgiou H M, Bellgrau D. Thymus transplantation and disease prevention in the diabetes-prone Bio-Breeding rat.  J Immunol. 1989;  142 3400-3405
• 39 Georgiou H M, Mandel T E. Induction of insulitis in athymic (nude) mice. The effect of NOD thymus and pancreas transplantation.  Diabetes. 1995;  44 49-59
• 40 Hosaka N, Nose M, Kyogoku M, Nagata N, Miyashima S, Good R A, Ikehara S. Thymus transplantation, a critical factor for correction of autoimmune disease in aging MRL/+ mice.  Proc Natl Acad Sci USA. 1996;  93 8558-8562
• 41 Thomas-Vaslin V, Damotte D, Coltey M, Le Douarin N M, Coutinho A, Salaün J. Abnormal T-cell selection on NOD thymic epithelium is sufficient to induce autoimmune manifestations in C57BL/6 athymic nude mice.  Proc Natl Acad Sci USA. 1997;  94 4598-4603
• 42 Savino W, Carnaud C, Luan J J, Bach J F, Dardenne M. Characterization of the extracellular matrix-containing giant perivascular spaces in the NOD mouse thymus.  Diabetes. 1993;  42 134-140
• 43 Doukas J, Mordes J P, Swymer C, Niedzwiecki D, Mason R, Rozing J, Rossini A A, Greiner D L. Thymic epithelial defects and predisposition to autoimmune disease in BB rats.  Am J Pathol. 1994;  145 1517-1525
• 44 Kecha-Kamoun O, Achour I, Martens H, Collette J, Lefebvre P J, Greiner D L, Geenen V. Thymic expression of insulin-related genes in an animal model of type 1 diabetes.  Diabetes/Metab Res Rev. 2001;  17 146-152
• 45 Brimnes M K, Jensen T, Jorgensen T N, Michelsen B K, Troelsen J, Werdenlin O. Low expression of insulin in the thymus of non-obese diabetic mice.  J Autoimmun. 2002;  19 203-213
• 46 Chentoufi A A, Polychronakos C. Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes.  Diabetes. 2002;  51 1383-1390
• 47 Thebault-Baumont K, Dubois-Laforgue D, Krief P, Briand J P, Halbout P, Vallon-Geoffroy K, Morin J, Laloux V, Lehuen A, Carel J C, Jami J, Muller S, Boitard C. Acceleration of type 1 diabetes in proinsulin 2 deficient mice.  J Clin Invest. 2003;  111 851-857
• 48 Kaufman D L, Clare-Salzler M C, Tian J, Forsthuber T, Ting G SP, Robinson P, Atkinson M A, Sercarz E E, Tobin A J, Lehmann P V. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes.  Nature. 1993;  366 69-72
• 49 Diez J, Park Y, Zeller M, Brown D, Garza D, Ricordi C, Hutton J, Eisenbarth G S, Pugliese A. Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen.  Diabetes. 2001;  50 895-900
• 50 Nagamine K, Peterson P, Scott H S, Kudoh J, Minoshima S, Heino M, Krohn K JE, Lalioti M D, Mullis P E, Antonorakis S E, Kawasaki K, Asakawa S, Ito F, Shimizu N. Positional cloning of the APECED gene.  Nat Genet. 1997;  17 393-398
• 51 Rossier M L, Heino M, Peterson P, Krohn K J, Gos A, Morris M A, Kudoh J, Shimizu N, Antonarakis S E, Scott H S. Isolation and characterization of the mouse Aire gene.  Biochem Biophys Res Commun. 1999;  255 483-490
• 52 Pitkänen J, Peterson P. Autoimmune regulator: from loss of function to autoimmunity.  Genes and Immunity. 2003;  4 12-21
• 53 Zuklys S, Balciunaite G, Agarwal A, Farler-Kan E, Palmer E, Holländer G A. Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).  J Immunol. 2000;  165 1976-1983
• 54 Heino M, Peterson P, Silanpää N, Guerin S, Wu L, Anderson G, Scott H S, Antonarakis S E, Kudoh J, Shimizu N, Jenkinson E J, Naquet P, Krohn K J. RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse.  Eur J Immunol. 2000;  30 1884-1893
• 55 Anderson M S, Venanzi E S, Klein L, Chen Z, Berzins S P, Turley S J, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D. Projection of an immunological self shadow in the thymus by the Aire protein.  Science. 2002;  298 1395-1301
• 56 Liston A, Lesage S, Wilson J, Peltonen L, Goodnow C C. Aire regulates negative selection of organ-specific T-cells.  Nat Immunol. 2003;  4 350-354
• 57 Burnet F M. A reassessment of the forbidden clone hypothesis of autoimmune diseases.  Aust J Exp Biol Med Sci. 1973;  50 1-9
• 58 Gottlieb P A, Eisenbarth G S. Insulin-specific tolerance in diabetes.  Clin Immunol. 2002;  102 2-11
• 59 Liu E, Moriyama H, Abiru N, Miao D, Yu L, Taylor R M, Finkelman F D, Eisenbarth G S. Anti-peptide antibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9 - 23 and B: 13 - 23.  J Clin Invest. 2002;  110 1021-1027
• 60 Chaillous L, Lefevre H, Thivolet C, Boitard C, Lahlou N, Atlan-Gegner C, Bouhanick B, Mogenet A, Nicolino M, Carel J C, Lecomte P, Marchenaud R, Bougneres P, Charbonnel B, Sai P. Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomized controlled trial. Diabetes Insulin Oral Group.  Lancet. 2000;  356 545-549
• 61 Pozzilli P, Pitocco D, Visalli N, Cavallo M G, Buzzetti R, Crino A, Spera S, Suraci C, Multari G, Cervoni M, Manca Bitti M L, Matteoli M C, Marietti G, Ferrazzoli F, Cassone Faldetta M R, Giordano C, Sbriglia M, Sarugeri E, Ghirlanda G. No effect of oral insulin on residual beta-cell function in recent-onset type 1 diabetes.  Diabetologia. 2000;  43 1000-1004
• 62 DPT-Type 1 diabetes Study Group . Effects of insulin in relatives of patients with type 1 diabetes.  N Engl J Med. 2002;  346 1685-1691
• 63 Alleva D G, Crowe P D, Jin L, Kwok V W, Ling N, Gottschalk M, Conlon P J, Gottlieb P A, Putman A L, Gaur A. A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin.  J Clin Invest. 2001;  107 173-180
• 64 Geenen V, Brilot F, Hansenne I, Louis C, Martens H, Wücherpfennig K, Gorus F. Thymus tolerance dysfunction in the development of the autoimmune diabetogenic response: a way for a novel type of vaccine/immunotherapy.  Diabetologia. 2003;  46 (suppl. 2) A10, abstract 22
• 65 Nossal G JV. Vaccination and autoimmunity.  J Autoimmun. 2000;  14 13-15
• 66 Geenen V, Poulin J F, Dion M L, Martens H, Castermans E, Hansenne I, Moutschen M, Sekaly R P, Cheynier R. Quantification of T-cell receptor rearrangement excision circles to estimate thymic function: an important new tool for endocrine-immune physiology.  J Endocrinol. 2003;  176 305-311
• 67 Kong F K, Kong F, Chen C H, Cooper M D. Thymic function can be accurately monitored by the level of recent T-cell emigrants in the circulation.  Immunity. 1998;  8 97-104
• 68 Douek D C, McFarland R D, Keiser P H, Gage E A, Massey J M, Haynes B F, Polis M A, Haase A T, Feinberg M B, Sullivan J L, Jamieson B D, Zack J A, Picker L J, Koup R A. Changes in thymic function with age and during the treatment of HIV infection.  Nature. 1998;  396 690-695
• 69 Poulin J F, Viswanathan M N, Harris J M, Kumanduri K V, Wieder E, Rinquette N, Jenkins M, McCune J M, Sekaly R P. Direct evidence for thymic function in adult humans.  J Exp Med. 1999;  190 479-486
• 70 McEndy D P, Boon M C, Furth J. On the role of thymus, spleen, and gonads in the development of leukemia in a high-leukemia stock of mice.  Cancer Res. 1944;  4 377-383
• 71 Metcalf D. In: Outstanding Papers in Biology. London; Current Biology Ltd 1993: 117-124
• 72 Petridou E, Klimentopoulou A E, Moustaki M, Kostrikis L G, Hatzakis A, Trichopoulos D. Recent thymic emigrants and prognosis in T- and B-cell childhood hematopoietci malignancies.  Int J Cancer. 2002;  101 74-77
• 73 von Boehmer H, Aifantis I, Feinberg J, Lechner O, Saint-Ruf C, Walter U, Buer J, Azogui O. Pleiotropic changes controlled by the pre-T-cell receptor.  Curr Opin Immunol. 1999;  11 135-142
• 74 Jameson S, Bevan M. T-cell selection.  Curr Opin Immunol. 1998;  10 214-219
• 75 Bellavia D, Campese A F, Alesse E, Vacca A, Felli M P, Balestri A, Stoppacciaro A, Tiveron C, Tatangelo L, Giovarelli M, Gaetano C, Ruco L, Hoffman E S, Hayday A C, Lendahl U, Frati L, Gulino A, Screpanti I. Constitutive activation of NF-κB and T-cell leukemia/lymphoma in Notch3 transgenic mice.  EMBO J. 2000;  19 3337-3348
• 76 Bellavia D, Campese A F, Checquolo S, Balestri A, Biondi A, Cazzaniga G, Lendahl U, Fehling H J, Hayday A C, Frati L, von Boehmer H, Gulino A, Screpanti I. Combined expression of pToc and Notch3 in T-cell leukemia identifies the requirement of preTCR for leukemogenesis.  Proc Natl Acad Sci USA. 2002;  99 3788-2793
• 77 Amsen D, Kruisbeek A M. Thymocyte selection: not by TCR alone.  Immunol Rev. 1998;  165 209-229
• 78 Pansky B, House E L, Cone L A. An insulin-like thymic factor. A preliminary report.  Diabetes. 1965;  14 325-332
• 79 Silverstein M N, Wakim K, Bahn R C, Bayrd E D. A hypoglycemic factor in leukemic tumors.  Proc Soc Exp Biol Med. 1960;  103 824-826
• 80 Zapf J, Hauri C, Waldvogel M, Froesch E R. Acute metabolic effects and half-lives of intravenously administered insulin-like growth factors I and II in normal and hypophectomised rats.  J Clin Invest. 1986;  77 1768-1775
• 81 Kooijman R K, Scholtens L E, Rijkers G T, Zegers B J. Differential expression of type I insulin-like growth factor receptors in different stages of human T-cells.  Eur J Immunol.. 1995;  25 931-935
• 82 Hansenne I, Rasier G, Charlet-Renard C, Defresne M P, Greimers R, Breton C, Legros J J, Geenen V, Martens H. Neurohypophysial receptor gene expression by thymic T-cell subsets and thymic T-cell lymphoma cell lines.  Dev Immunol. 2003;  in press
• 83 Mason D Y. Seventh Workshop on Human Leukocyte Differentiation Antigens,. 2000