Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse

Abstract

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 NOD͞BDC2.5 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)1͞Th2 balance because lymphocytes purified from lymphoid organs and pancreatic islets of wild-type and CD1d-null mice secreted equivalent amounts of IFN-␥ 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.

Transforming Growth Factor-β and Natural Killer T-Cells Are Involved in the Protective Effect of a Bacterial Extract on Type 1 Diabetes

“…The data presented in this article confirm that NKT cells are implicated in type 1 diabetes. One should mention, however, that in our present study, both mouse strains (CD1d Ϫ/Ϫ and wild type) showed a similar type 1 diabetes incidence, a finding in clear contrast with another report (37), but in the line of that of Van Kaer (38), who provided us with the mice used here. If NKT cells are indeed involved in the OM-85-mediated protection, it will be important to determine which component within OM-85 stimulates NKT cells and what mechanisms mediate NKT cell involvement.…”

Genetic Dissection of Vα14Jα18 Natural T Cell Number and Function in Autoimmune-Prone Mice

“…Further, increasing the number of endogenous iNKT cells through V␣14J␣18 TCR transgenesis increases IL-4 production by NOD transgenics and protects them from TID (30). Moreover, the absence of NKT cells in NOD.129-CD1d 0/0 mice increased TID incidence (9,31) even in males, which ordinarily have delayed onset and relatively lower disease incidence compared with female NOD mice (9). Together these findings underscore the role of iNKT cells in downregulating autoimmune responses in vivo.…”

Immunoregulation of Autoimmunity by Natural Killer T Cells

“…The genetic control of NKT cell numbers in NOD mice was mapped to type 1 diabetes loci [71]. CD1d deficient mice developed diabetes earlier, had a greater disease penetrance and more severe disease [72,73]. In concordance, upregulation of CD1d expression restored the immunoregulatory function of NKT cells and prevented autoimmune diabetes [74].…”