T cell reactivity to heat shock protein 60 in diabetes-susceptible and genetically protected nonobese diabetic mice is associated with a protective cytokine profile.
Spontaneous onset of pancreatic beta cell destruction in the nonobese diabetic (NOD) mouse is preceded by the induction of autoreactive T cells, which recognize a variety of autoantigens. The 60-kDa endogenous (murine) heat shock protein 60 (hsp60) has been proposed to be one of the key autoantigens. Here we demonstrate that subcutaneous immunization of normoglycemic NOD mice with highly homologous mycobacterial or murine hsp60 activates T cells in the spleen that produce high levels of IL-10 upon restimulation in vitro with either hsp60 protein. In time, increasing levels of hsp60-induced IL-10 could be detected in NOD mice, but not in age- and MHC class II-matched BiozziABH mice, which lack any sign of pancreatic inflammation. These results suggest that the IL-10 responses in NOD mice are primarily driven by endogenous inflammation. Genetically protected NOD-asp mice, showing a less progressive development of insulitis, demonstrated a similar increase in hsp60-induced IL-10 in time compared with wild-type NOD mice. Taken together, our results suggest that endogenous hsp60 is not a primary autoantigen in diabetes but is possibly associated with regulation of insulitis. Moreover, the capacity to respond to (self) hsp60 is independent of the MHC class II-associated genetic predisposition to diabetes.
van Halteren
A G
AG
Department of Cell Biology and Immunology, Medical Faculty, Vrije Universiteit Amsterdam, Amsterdam. agsvanhalteren@lumc.nl
Mosselman
B
B
Roep
B O
BO
van Eden
W
W
Cooke
A
A
Kraal
G
G
Wauben
M H
MH
D000818:Animals; D018834:Chaperonin 60 / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006650:Histocompatibility Testing; D016753:Interleukin-10 / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000276:immunology; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D018834:Chaperonin 60; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D016753:Interleukin-10