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.
Key words
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 4th 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 3rd 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
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