Development of the Dendritic Cell System during Mouse Ontogeny

A model of neonatal autoimmune disease has been described recently in which an epitope-specific autoantibody to murine zona pellucida 3 induces severe ovarian disease in neonatal, but not adult, mice (neonatal AOD). The autoantibody forms immune complex with endogenous ovarian zona pellucida 3, and a pathogenic CD4+ T cell response is triggered. The basis for the predominant neonatal susceptibility has not been clarified. In this study innate immunity, including neonatal NK cells, in neonatal AOD was investigated. Neonatal spleen contained readily detectable NK1.1+TCRVβ−, but not NK1.1+TCRVβ+, cells. Ab depletion of NK1.1+TCRVβ− cells inhibited neonatal AOD development. Moreover, in adoptive transfer of neonatal AOD, recipient disease was ameliorated when either donor or recipient NK cells were depleted. Thus, NK cells operate in both induction and effector phases of the disease. IFN-γ was produced by neonatal NK cells in vivo, and it may be important in neonatal AOD. Indeed, ovaries with neonatal AOD expressed high levels of IFN-γ and TNF-α which correlated with disease severity, and the disease was inhibited by IFN-γ or TNF-α Ab. Importantly, disease was enhanced by recombinant IFN-γ, and treatment of T cell donors with IFN-γ Ab also significantly reduced adoptive transfer of neonatal AOD. Finally, neonatal AOD was ameliorated in mice deficient in FcγRIII and was enhanced in FcγRIIB-deficient mice. We conclude that neonatal NK cells promote pathogenic T cell response at multiple stages during neonatal autoimmune disease pathogenesis. Also operative in neonatal AOD are other mediators of the innate system, including proinflammatory cytokines and FcγRIII signaling.

Section: Figurementioning

confidence: 99%

Requirements of NK Cells and Proinflammatory Cytokines in T Cell-Dependent Neonatal Autoimmune Ovarian Disease Triggered by Immune Complex

Setiady¹,

Pramoonjago²,

Tung

2004

“…1A). Total CD11c int/hi MHC-II int/hi CD11b int/hi DC numbers (i.e., blood-derived and skin/tissue-derived DC) (23,24) peaked at day 4 p.i. (Fig.…”

Section: Changes In the Aln And Skin Following Wnv Infectionmentioning

confidence: 99%

Accelerated Dendritic Cell Differentiation from Migrating Ly6Clo Bone Marrow Monocytes in Early Dermal West Nile Virus Infection

Davison

King

2011

No study has investigated the participation of Ly6C+ monocytes in the earliest phase of skin infection with the mosquito-borne West Nile virus. In a novel murine model mimicking natural dermal infection, CCL2-dependent bone marrow (BM)-derived monocyte migration, differentiation into Ly6C+ dendritic cells (DC), and accumulation around dermal deposits of infected fibroblasts by day 1 postinfection were associated with increasing numbers of monocyte-derived TNF/inducible NO synthase-producing DC by day 2 postinfection in draining auricular lymph nodes (ALN). Adoptive transfer demonstrated simultaneous migration of bone marrow-derived Ly6Clo monocytes to virus-infected dermis and ALN, where they first become Ly6Chi DC within 24 h and then Ly6Clo DC by 72 h. DC migration from the infected dermis to the ALN derived exclusively from Ly6Clo BM monocytes. This demonstrates that Ly6Chi and Ly6Clo BM-derived monocytes have different fates in vivo and suggests that BM may be a reservoir of preinflammatory monocytes for rapid deployment as inflammatory DC during virus infection.

“…Although newborn mice have few CD11c ϩ cells and mature DC do not fully develop until 5 wk of age (35), thymus and spleen cells from newborn wild-type and Ins1 Ϫ/Ϫ Ins2 Ϫ/Ϫ mice stained with the polyclonal Ab to GAD. Thus, PAE cells were present at birth, although possibly not fully matured.…”

Section: Proinsulin Surface Staining Depends On Insulin Gene Transcrimentioning

confidence: 99%

Dendritic Cells in Human Thymus and Periphery Display a Proinsulin Epitope in a Transcription-Dependent, Capture-Independent Fashion

García¹,

Prabakar²,

Díez³

et al. 2005

The natural expression of tissue-specific genes in the thymus, e.g., insulin, is critical for self-tolerance. The transcription of tissue-specific genes is ascribed to peripheral Ag-expressing (PAE) cells, which discordant studies identified as thymic epithelial cells (TEC) or CD11c+ dendritic cells (DC). We hypothesized that, consistent with APC function, PAE-DC should constitutively display multiple self-epitopes on their surface. If recognized by Abs, such epitopes could help identify PAE cells to further define their distribution, nature, and function. We report that selected Abs reacted with self-epitopes, including a proinsulin epitope, on the surface of CD11c+ cells. We find that Proins+CD11c+ PAE cells exist in human thymus, spleen, and also circulate in blood. Human thymic Proins+ cells appear as mature DC but express CD8α, CD20, CD123, and CD14; peripheral Proins+ cells appear as immature DC. However, DC derived in vitro from human peripheral blood monocytes include Proins+ cells that uniquely differentiate and mature into thymic-like PAE-DC. Critically, we demonstrate that human Proins+CD11c+ cells transcribe the insulin gene in thymus, spleen, and blood. Likewise, we show that mouse thymic and peripheral CD11c+ cells transcribe the insulin gene and display the proinsulin epitope; moreover, by using knockout mice, we show that the display of this epitope depends upon insulin gene transcription and is independent of Ag capturing. Thus, we propose that PAE cells include functionally distinct DC displaying self-epitopes through a novel, transcription-dependent mechanism. These cells might play a role in promoting self-tolerance, not only in the thymus but also in the periphery.