Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse.
Quantitative and qualitative defects in CD1-restricted natural killer T cells have been reported in several autoimmune-prone strains of mice, including the nonobese diabetic (NOD) mouse. These defects are believed to be associated with the emergence of spontaneous autoimmunity. Here we demonstrate that both CD1d-null NOD and CD1d-null NOD/BDC2.5 T cell receptor transgenic mice have an accelerated onset and increased incidence of diabetes when compared with CD1d(+/-) and CD1d(+/+) littermates. The acceleration of disease did not seem to result from changes in the T helper (Th)1/Th2 balance because lymphocytes purified from lymphoid organs and pancreatic islets of wild-type and CD1d-null mice secreted equivalent amounts of IFN-gamma and IL-4 after stimulation. In contrast, the pancreata of CD1d-null mice harbored significantly higher numbers of activated memory T cells expressing the chemokine receptor CCR4. Notably, the presence of these T cells was associated with immunohistochemical evidence of increased destructive insulitis. Thus, CD1d-restricted T cells are critically important for regulation of the spontaneous disease process in NOD mice.
Shi
F D
FD
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Flodstrom
M
M
Balasa
B
B
Kim
S H
SH
Van Gunst
K
K
Strominger
J L
JL
Wilson
S B
SB
Sarvetnick
N
N
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics*; D055610:Antigens, CD1d; D002874:Chromosome Mapping; D003920:Diabetes Mellitus / Q000209:etiology*; D005260:Female; D007156:Immunologic Memory; D007694:Killer Cells, Natural / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054398:Receptors, CCR4; D019713:Receptors, CCR5 / Q000032:analysis; D019707:Receptors, Chemokine / Q000032:analysis; D018417:Th1 Cells / Q000502:physiology; D018418:Th2 Cells / Q000502:physiology
D018949:Antigens, CD1; D055610:Antigens, CD1d; C515355:Ccr4 protein, mouse; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D019707:Receptors, Chemokine