Activation of CD1d-restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets

Naumov, Yuri N.; Bahjat, Keith S.; Gausling, Rudolf; Abraham, R.; Exley, Mark A.; Koezuka, Yasuhiko; Balk, Silke; Strominger, Jack L.; Clare-Salzer, M; Wilson, S. Brian

doi:10.1073/pnas.251531798

Cited by 277 publications

(303 citation statements)

References 45 publications

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“…Consistent with a protective role of CD1d-reactive T cells, patients with SLE also have a selective reduction of NKT cells [17][18][19]. Finally, activation of these cells can reduce autoantibody production and protect against various immune-mediated diseases including type 1 diabetes and experimental autoimmune encephalomyelitis [20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 81%

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CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

et al. 2004

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Mechanisms responsible for the development of autoimmune skin disease in humans and animal models with lupus remain poorly understood. In this study, we have investigated the role of CD1d, an antigen-presenting molecule known to activate natural killer T cells, in the development of inflammatory dermatitis in lupus-susceptible MRL-lpr/lpr mice. In particular, we have established MRL-lpr/lpr mice carrying a germ-line deletion of the CD1d genes. We demonstrate that CD1d-deficient MRL-lpr/lpr mice, as compared with wild-type littermates, have more frequent and more severe skin disease, with increased local infiltration with mast cells, lymphocytes and dendritic cells, including Langerhans cells. CD1d-deficient MRL-lpr/ lpr mice had increased prevalence of CD4 + T cells in the spleen and liver and of TCR § g + B220 + cells in lymph nodes. Furthermore, CD1d deficiency was associated with decreased T cell production of type 2 cytokines and increased or unchanged type 1 cytokines. These findings indicate a regulatory role of CD1d in inflammatory dermatitis. Understanding the mechanisms by which CD1d deficiency results in splenic T cell expansion and cytokine alterations, with increased dermal infiltration of dendritic cells and lymphocytes in MRL-lpr/lpr mice, will have implications for the pathogenesis of inflammatory skin diseases.

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Section: Introductionmentioning

confidence: 81%

“…There is evidence of significant cross-talk between CD1d-reactive T cells and dendritic cells [40,41], resulting in alterations in the differentiation/maturation of dendritic cell subsets, which may contribute to modulation of autoimmune responses [22]. CD40/CD40L interactions may play an important role in this cross-talk [41].…”

Section: Discussionmentioning

confidence: 99%

CD1d deficiency exacerbates inflammatory dermatitis in MRL‐lpr/lpr mice

et al. 2004

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“…It has been well established that activation of iNKT cells by repeated aGalCer injections prevents the development of diabetes in NOD mice [8,10,15]. Autoimmunity prevention correlated with the ability of aGalCer to induce iNKT cell anergy and to strongly suppress their IFN-g production while IL-4 production was less inhibited [33].…”

Section: Cd4 à Inkt Cells Containing Inkt17 Cells Enhance the Incidenmentioning

confidence: 97%

“…However, following studies using the transfer of anti-islet T cells showed that iNKT cells inhibit the differentiation of these auto-reactive T cells into effector cells during their priming in pancreatic lymph nodes (PLNs) [13,14]. This regulatory role of iNKT cells could be explained by their ability to promote the recruitment of tolerogenic DCs [14,15].…”

Section: Introductionmentioning

confidence: 99%

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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Invariant natural killer T (iNKT) cells are a distinct lineage of innate-like T lymphocytes and converging studies in mouse models have demonstrated the protective role of iNKT cells in the development of type 1 diabetes. Recently, a new subset of iNKT cells, producing high levels of the pro-inflammatory cytokine IL-17, has been identified (iNKT17 cells). Since this cytokine has been implicated in several autoimmune diseases, we have analyzed iNKT17 cell frequency, absolute number and phenotypes in the pancreas and lymphoid organs in non-obese diabetic (NOD) mice. The role of iNKT17 cells in the development of diabetes was investigated using transfer experiments. NOD mice exhibit a higher frequency and absolute number of iNKT17 cells in the lymphoid organs as compared with C57BL/6 mice. iNKT17 cells infiltrate the pancreas of NOD mice where they express IL-17 mRNA. Contrary to the protective role of CD4 1 iNKT cells, the CD4 À iNKT cell population, which contains iNKT17 cells, enhances the incidence of diabetes. Treatment with a blocking anti-IL-17 antibody prevents the exacerbation of the disease. This study reveals that different iNKT cell subsets play distinct roles in the regulation of type 1 diabetes and iNKT17 cells, which are abundant in NOD mice, exacerbate diabetes development.

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“…DC tolerogenicity manifested as the suppression of T-cell activation has been documented in tumor, allo-and autoimmunity. 90 Therapeutics 90,[94][95][96][97][98] With the aim of establishing a durable tolerogenic state in the recipient of an allogeneic transplant, myeloid DC have been genetically modified using adenoviral and retroviral vectors encoding CTLA-4Ig, TGF-b and IL-10 in the mouse. [91][92][93] .…”

Section: Case For DCmentioning

confidence: 99%