Immunoglobulin E Production in the Absence of Interleukin-4-Secreting CD1-Dependent Cells

Nonobese diabetic (NOD) mice, a model for type I diabetes (TID), have reduced numbers of invariant Vα14Jα18 TCR α-chain-positive natural T (iNKT) cells that do not release IL-4 in response to in vivo activation through their Ag receptor. The deficit in iNKT cell number and function is implicated in immune dysregulation and the etiology of TID. Therefore, we reasoned that the genetic determinant(s) that controls iNKT cell number and function might lie within Idd (insulin-dependent diabetes susceptibility locus) regions, which are known to contain TID resistance or susceptibility genes. A systematic analysis of iNKT cell number and function in Idd congenic mice revealed that neither iNKT cell number nor their inability to rapidly secrete IL-4 in response to acute in vivo activation by Ag underlies the mechanism of protection from diabetes in Idd congenic mice. Moreover, the regulation of iNKT cell number and function appears to be under the control of several genes. The most notable of these map to the Idd4, Idd5, Idd9.1, and Idd13 regions of the mouse genome. Together these findings provide a clue to the genetic mechanism(s) underlying iNKT cell deficiency in NOD mice.

Section: Tid-resistant Nor and Tid-susceptible Nod Mice Have Similar mentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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

Matsuki

Stanic

Embers

et al. 2003

“…Part of the NKT phenotype (display of CD122/IL-2R␤) appears to be a result of the selection process, while expression of the NK1.1 marker itself may result from an independent event taking place at a later time. Findings from various mutant mice suggest a division of NKT development into a first step of CD1d-dependent selection (31,52,53), leading to the CD122 ϩ phenotype, and a second, cytokine-dependent step resulting in final maturation of NKT cells characterized by the expression of NK1.1 (54,55). Further, some of the 24␣ ϩ ␤ ϩ CD122 ϩ NK1.1 Ϫ cells may have lost expression of the NK1.1 marker during activation (44).…”

Section: Discussionmentioning

confidence: 99%

CD1d-Specific NK1.1+ T Cells with a Transgenic Variant TCR

Sköld

Faizunnessa

Wang

et al. 2000

The majority of T lymphocytes carrying the NK cell marker NK1.1 (NKT cells) depend on the CD1d molecule for their development and are distinguished by their potent capacity to rapidly secrete cytokines upon activation. A substantial fraction of NKT cells express a restricted TCR repertiore using an invariant TCR Vα14-Jα281 rearrangement and a limited set of TCR Vβ segments, implying recognition of a limited set of CD1d-associated ligands. A second group of CD1d-reactive T cells use diverse TCR potentially recognizing a larger diversity of ligands presented on CD1d. In TCR-transgenic mice carrying rearranged TCR genes from a CD1d-reactive T cell with the diverse type receptor (using Vα3.2/Vβ9 rearrangements), the majority of T cells expressing the transgenic TCR had the typical phenotype of NKT cells. They expressed NK1.1, CD122, intermediate TCR levels, and markers indicating previous activation and were CD4/CD8 double negative or CD4+. Upon activation in vitro, the cells secreted large amounts of IL-4 and IFN-γ, a characteristic of NKT cells. In mice lacking CD1d, TCR-transgenic cells with the NKT phenotype were absent. This demonstrates that a CD1d-reactive TCR of the “non-Vα 14” diverse type can, in a ligand-dependent way, direct development of NK1.1+ T cells expressing expected functional and cell-surface phenotype characteristics.

“…We therefore wondered whether increased resistance of LFA-1 Ϫ/Ϫ mice to low dose LPS-induced shock was due to the reduction of V␣14 ϩ NKT cells in the liver. To clarify this issue, the susceptibilities of TCR␤ Ϫ/Ϫ , ␤ 2 m Ϫ/Ϫ , and CD1d Ϫ/Ϫ mice, all of which are devoid of V␣14 ϩ NKT cells (20,(33)(34)(35)(36), to low dose LPS-induced shock were compared. The susceptibilities of TCR␤ Ϫ/Ϫ and CD1d Ϫ/Ϫ mice to low dose LPS-induced shock were comparable to that of C57BL/6 mice, and susceptibility was slightly increased in ␤ 2 m Ϫ/Ϫ mice (Table I).…”

Section: V␣14 ϩ Nkt Cells Granulocytes and Tissue Macrophages Are Nmentioning

confidence: 99%

Increased Resistance of LFA-1-Deficient Mice to Lipopolysaccharide-Induced Shock/Liver Injury in the Presence of TNF-α and IL-12 Is Mediated by IL-10: A Novel Role for LFA-1 in the Regulation of the Proinflammatory and Anti-Inflammatory Cytokine Balance

Emoto¹,

Emoto²,

Brinkmann

et al. 2003

Challenge with low doses of LPS together with d-galactosamine causes severe liver injury, resulting in lethal shock (low dose LPS-induced shock). We examined the role of LFA-1 in low dose LPS-induced shock. LFA-1−/− mice were more resistant to low dose LPS-induced shock/liver injury than their heterozygous littermates, although serum levels of TNF-α and IL-12 were higher in these mice. C57BL/6 mice were not rescued from lethal effects of LPS by depletion of NK1+ cells, granulocytes, or macrophages, and susceptibility of NKT cell-deficient mice was comparable to that of controls. High numbers of platelets were detected in the liver of LFA-1+/− mice after low dose LPS challenge, whereas liver accumulation of platelets was only marginal in LFA-1−/− mice. Following low dose LPS challenge, serum levels of IL-10 were higher in LFA-1−/− mice than in LFA-1+/− mice, and susceptibility to low dose LPS-induced shock as well as platelet accumulation in the liver of LFA-1−/− mice were markedly increased by IL-10 neutralization. Serum levels of IL-10 in LFA-1+/− mice were only marginally affected by macrophage depletion. However, in LFA-1−/− mice macrophage depletion markedly reduced serum levels of IL-10, and as a corollary, susceptibility of LFA-1−/− mice to low dose LPS-induced shock was markedly elevated despite the fact that TNF-α levels were also diminished. We conclude that LFA-1 participates in LPS-induced lethal shock/liver injury by regulating IL-10 secretion from macrophages and that IL-10 plays a decisive role in resistance to shock/liver injury. Our data point to a novel role of LFA-1 in control of the proinflammatory/anti-inflammatory cytokine network.