Absolute requirement of macrophages for the development and activation of beta-cell cytotoxic CD8+ T-cells in T-cell receptor transgenic NOD mice.

Lee, Youn-Jung; Santamaría, Pere; Lim, Hoyong; Zhang, Mei Luo; Yoon, Ji‐Won

doi:10.2337/diabetes.48.1.34

Cited by 86 publications

(70 citation statements)

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“…Macrophages are the first cells to infiltrate the islets in both NOD mice and BB rats [6,57]. Activated macrophages are toxic to pancreatic islets in vitro [58] and macrophage depletion or inactivation prevent diabetes in BB rats and NOD mice [59,60]. IP-10 was reported to attract monocytes [61], and it is therefore conceivable that the early expression of IP-10 (current data) and MCP-1 [8] by NOD islet cells contributes to the recruitment of macrophages in the early stages of insulitis.…”

Section: Discussionmentioning

confidence: 99%

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

et al. 2003

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Aims/hypothesis. Cytokines and chemokines are important mediators of immune responses due to their ability to recruit and activate leukocytes. Using microarray analysis we observed that rat beta cells exposed to IL-1β and IFN-γ have increased mRNA levels of chemokines and IL-15. The aim of this study was to characterize the expression of IP-10, MIP-3α, fractalkine and IL-15 in rat beta cells, human pancreatic islets, and in islets isolated from NOD mice, both during the pre-diabetic period and following islet transplantation. Methods. FACS-purified rat beta cells and human islets were cultured with IL-1β, IFN-γ and/or TNF-α. Islets were isolated from NOD or BALB/c mice at different ages. For syngeneic islet transplantation, 2-or 3-week-old NOD islets were grafted under the kidney capsule of spontaneously diabetic NOD recipients. Chemokine and IL-15 mRNA expression and protein release were evaluated, respectively, by RT-PCR and ELISA.Results. Human islets and rat beta cells express IP-10, MIP-3α, fractalkine and IL-15 mRNAs upon exposure to cytokines. The expression of IL-15, IP-10 and fractalkine is regulated by IFN-γ, while the expression of MIP-3α is IL-1β-dependent. Moreover, cytokines induced IL-15, IP-10, Mig, I-TAC and MIP-3α protein accumulation in culture medium from human islets. In vivo, there was an age-related increase in IL-15, IP-10 and MIP-3α expression in islets isolated from NOD mice. Following syngeneic islet transplantation, increased expression of IL-1β, IFN-γ, fractalkine, IP-10, MCP-1 and MIP-3α mRNAs were observed in the grafts. Conclusion/interpretation. Cytokine-exposed islets or beta cells express chemokines and IL-15. This could contribute to the recruitment and activation of mononuclear cells and development of insulitis in early Type 1 diabetes and during graft destruction. [Diabetologia (2003) 46:255-266] Keywords Type 1 diabetes mellitus, chemokines, IL-15, NOD mice, beta cells, interferon-γ, interleukin-1β, pancreatic islets, islet transplantation, insulitis.

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Section: Discussionmentioning

confidence: 99%

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

et al. 2003

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“…In support of this hypothesis, it was recently shown that T cell-derived IFN-␥ is essential for the rejection of tumor allografts, and that this requirement is due to the ability of IFN-␥ to activate cytotoxic macrophages at the graft site (57). Similarly, islet-specific autoimmune pathogenesis by CD8 ϩ T cells in a transgenic model has been shown to be macrophage dependent (58).…”

Section: Discussionmentioning

confidence: 99%

An Essential Contribution by IFN-γ to CD8+ T Cell-Mediated Rejection of Pancreatic Islet Allografts

Diamond¹,

Gill

2000

The Journal of Immunology

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CD8+ T cells have long been considered to be the prototypical cytotoxic lymphocyte subpopulation. However, whether alloreactive CD8+ T cells require traditional cytolytic pathways such as perforin and Fas ligand (FasL) to mediate graft rejection has been a controversial issue. In the present studies, we examined the role of varied effector pathways in CD8+ T cell-mediated rejection of pancreatic islet allografts. Our goal was to systematically determine the relative requirements, if any, of perforin and FasL as well as the proinflammatory cytokine IFN-γ in triggering graft destruction. To study CD8+ T cell effector pathways independently of other lymphocyte populations, purified alloreactive CD8+ T cells were adoptively transferred into severe combined immune-deficient (SCID) recipients bearing established islet allografts. Results indicate that to reject established islet allografts, primed CD8+ T cells do not require the individual action of the conventional cytotoxic effectors perforin and Fas ligand. In contrast, the ability to produce IFN-γ is critical for efficient CD8+ T cell-mediated rejection of established islet allografts. Furthermore, alloreactive CD8+ TCR transgenic T cells (2C) also show IFN-γ dependence for mediating islet allograft rejection in vivo. We speculate from these results that the production of IFN-γ by alloreactive CD8+ T cells is a rate-limiting step in the process of islet allograft rejection.

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“…29,37 Other groups used clodronate-dependent elimination of macrophages in NOD mice to demonstrate protection from diabetes. 34,39 Here again, young NOD mice that were depleted of macrophages were unable to generate cytotoxic T cells, thereby implicating the macrophage as an essential accessory cell for the differentiation of effector diabetogenic T cells. 34 Moreover, as seen in the previous studies with silica administration, the clodronate-treated NOD mice also exhibited protection from insulitis, 34 which was in agreement with the lack of priming of diabetogenic T cells responsible for recruitment of the inflammatory infiltrate in the pancreas.…”

Section: Macrophages Kill ␤ Cells In T1dm 2143mentioning

confidence: 99%

“…29,34,38,39 Several studies in the past suggested that inhibition of diabetes in macrophagedepleted NOD mice was a likely result of impaired priming and expansion of diabetogenic CD4 ϩ and CD8 ϩ T cells, 34 -36,39 whereas other in vitro assays demonstrated that activated macrophages could lyse pancreatic ␤-tumor cells. 44 -46 For example, the result that depletion of macrophages via silica particles in NOD mice or BB rats resulted in protection from diabetes was interpreted to suggest an important role for macrophages in the priming of diabetogenic T cells.…”

Section: Macrophages Kill ␤ Cells In T1dm 2143mentioning

confidence: 99%

“…It is generally accepted that CD8 ϩ T-cell-mediated cytotoxicity of ␤ cells is a result of a direct interaction involving the Fas/FasL or the perforin/ granzyme pathway 8 -12 ; however, the observation that diabetogenic CD8 ϩ T cells in macrophage-depleted NOD mice are unable to induce diabetes suggests that the macrophage could also be operational in this situation. 39 CD8 ϩ T cells produce cytokines such as interferon-␥ that activate macrophages and may also activate the phagocytic cells to differentiate into islet ␤-cell killers.…”

Section: Macrophages Kill ␤ Cells In T1dm 2143mentioning

confidence: 99%

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In CD4+ T-Cell-Induced Diabetes, Macrophages Are the Final Effector Cells that Mediate Islet β-Cell Killing

Calderon

Suri

Unanue

2006

The American Journal of Pathology

111

113

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To understand better how diabetogenic CD4 ؉ T cells induce isletType 1 diabetes mellitus (T1DM) is an autoimmune disorder wherein the pancreatic islet ␤ cells are destroyed by autoreactive T cells resulting in a state of persistent hyperglycemia. The nonobese diabetic (NOD) mouse and the bio breeding (BB) rat are two attractive animal models for T1DM that follow many characteristics of the human disease including the expression of the diabetessusceptible class II major histocompatibility complex (MHC) alleles. 1-3 T1DM in both humans and rodents is characterized by distinct histopathological stages. The first stage, termed peri-insulitis, consists of an initial infiltration of leukocytes surrounding the islets without apparent effect on ␤ cells; this is followed by an aggressive phase wherein the infiltrate actively invades the islets and kills the ␤ cells, leading to diabetes. CD4 ϩ T cells are essential for development of diabetes by recognizing ␤-cell antigens in the context of the class II MHC I-A g7 . Involvement of CD8 ϩ T cells has also been extensively documented. 4 -7 Various mechanisms for inducing ␤-cell death have been proposed including a role for Fas/FasL, perforin/granzyme pathway, Rae1-NKG2D interaction, and reactive oxygen species induced by proinflammatory cytokines. 8 -12 A major hurdle in understanding the role of various leukocytes in T1DM is the large and varied time span between peri-insulitis and onset of diabetes (in NOD mice it can be anywhere between 10 to 14 weeks). Moreover, the presence of both CD4 ϩ and CD8 ϩ T cells makes it difficult to dissect the effector pathways used by each to induce islet ␤-cell death. To this end, we have examined an accelerated model of T1DM using the diabetogenic CD4 ϩ T cell, BDC2.5, expressed as a T-cell receptor (TCR) transgene in NOD mice (from here on referred to as BDC T cells). BDC T cells recognize an unidentified islet ␤-cell antigen presented by the I-A g7 class II MHC molecule of NOD mice. 13 Activated BDC T cells transfer diabetes into NOD.scid recipients in a short period of time with reproducible kinetics and incidence.

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Absolute requirement of macrophages for the development and activation of beta-cell cytotoxic CD8+ T-cells in T-cell receptor transgenic NOD mice.

Cited by 86 publications

References 0 publications

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

An Essential Contribution by IFN-γ to CD8+ T Cell-Mediated Rejection of Pancreatic Islet Allografts

In CD4+ T-Cell-Induced Diabetes, Macrophages Are the Final Effector Cells that Mediate Islet β-Cell Killing

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