A sudden decline in active membrane-bound TGF-beta impairs both T regulatory cell function and protection against autoimmune diabetes.
Autoimmunity presumably manifests as a consequence of a shortfall in the maintenance of peripheral tolerance by CD4(+)CD25(+) T regulatory cells (Tregs). However, the mechanism underlying the functional impairment of Tregs remains largely undefined. In this study a glutamic acid decarboxylase (GAD) diabetogenic epitope was expressed on an Ig to enhance tolerogenic function, and the resulting Ig-GAD expanded Tregs in both young and older insulitis-positive, nonobese diabetic (NOD) mice, but delayed autoimmune diabetes only in the former. Interestingly, Tregs induced at 4 wk of age had significant active membrane-bound TGF-beta (mTGF-beta) and sustained protection against diabetes, whereas Tregs expanded during insulitis had minimal mTGF-beta and could not protect against diabetes. The Tregs probably operate suppressive function through mTGF-beta, because Ab blockade of mTGF-beta nullifies protection against diabetes. Surprisingly, young Tregs that modulated pathogenic T cells maintained stable frequency over time in the protected animals, but decreased their mTGF-beta at the age of 8 wk. More strikingly, these 8-wk-old mTGF-beta-negative Tregs, which were previously protective, became unable to confer resistance against diabetes. Thus, a developmental decline in active mTGF-beta nullifies Treg function, leading to a break in tolerance and the onset of diabetes.
Gregg
Randal K
RK
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212, USA.
Jain
Renu
R
Schoenleber
Scott J
SJ
Divekar
Rohit
R
Bell
J Jeremiah
JJ
Lee
Hyun-Hee
HH
Yu
Ping
P
Zaghouani
Habib
H
D000375:Aging / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*
D018984:Epitopes, T-Lymphocyte; D008565:Membrane Proteins; D010455:Peptides; D016212:Transforming Growth Factor beta; D005968:Glutamate Decarboxylase