Autoimmune Diabetes Is Suppressed by Transfer of Proinsulin-Encoding Gr-1+ Myeloid Progenitor Cells That Differentiate In Vivo Into Resting Dendritic Cells

Steptoe, Raymond J.; Ritchie, Janine M.; Jones, Lynelle K.; Harrison, Leonard C.

doi:10.2337/diabetes.54.2.434

Cited by 50 publications

(35 citation statements)

References 48 publications

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“…36 Given our current observations that nonfunctional CD8 ϩ T cells, ie, failure to lyse or produce interferon-␥ when stimulated with minor H alloantigen, can also be expanded from some of our donors (&2, &3, and (2, data not shown), we speculate that naturally established tolerance to minor H antigens may be the result of either the presence of minor H antigen-specific T REG and/or the induction of T-cell anergy. Several experimental transplantation models have demonstrated that the establishment and maintenance of stable allograft tolerance depend on systemically persisting alloantigen-expressing microchimeric cell types, such as lymphocytes, 37,38 DCs, [39][40][41][42] or both. 17 These cell types continuously present alloantigen to host T cells under noninflammatory conditions, which may lead to active deletion of host alloreactive T cells 37 and/or the induction of alloreactive adaptive T REG .…”

Section: Discussionmentioning

confidence: 99%

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Halteren

Jankowska‐Gan

Joosten

et al. 2009

Blood

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Bidirectional cell transfer during pregnancy frequently leads to postpartum persistence of allogeneic cells and alloimmune responses in both the mother and in her offspring. The life-long consequences of naturally acquired alloimmune reactivity are probably of importance for the outcome of allogeneic stem cell transplantation. We investigated the presence of CD8 pos minor histocompatibility (H) antigen-specific cytotoxic T lymphocytes (T CTL ) and CD8 pos minor H antigen-specific T regulator cells (T REG ) in peripheral blood cells obtained from 17 minor H antigen-disparate mother-offspring pairs. Absence of minor H antigen-specific T REG , as marked by the feasibility to expand T CTL from isolated tetramer pos populations, was observed in 6 mothers and 1 son. The presence of minor H alloantigen-specific T REG was observed in 4 mothers and 5 sons.These T REG were detected within isolated tetramer dim staining fractions and functioned in a CTLA-4-dependent fashion. Our study indicates that both T CTL and T REG mediated alloimmunity against minor H antigens may be present in healthy female and male hematopoietic stem cell donors, potentially influencing graftversus-host reactivity in different ways.

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Section: Discussionmentioning

confidence: 99%

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Halteren

Jankowska‐Gan

Joosten

et al. 2009

Blood

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“…Conversely, the transgenic expression of Ins2 in MHC class II-positive cells, including in the thymus, prevents diabetes in NOD mice (13); moreover, syngeneic transplantation of transgenic BM expressing Ins2 in APC and the transfer of CD11c ϩ DC transgenically expressing Ins2 prevent diabetes in NOD mice (41,42). Thus, there is evidence from genetically manipulated mouse models that the expression of self-Ags in the thymus and by adoptively transferred BM-derived APC can influence self-tolerance.…”

Section: Discussionmentioning

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 Journal of Immunology

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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.

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“…Additional cell subsets of interest include GM precursors, which reportedly protect against GVHD (43). However, a similar population of CD11c Ϫ CD11b ϩ Gr-1 ϩ granulocyte-monocyte precursors was able to prevent diabetes in NOD mice only if they were expressing the autoantigen proinsulin as a transgene (90).…”

Section: Future Perspectivesmentioning

confidence: 99%

Granulocyte Colony-Stimulating Factor: A Novel Mediator of T Cell Tolerance

Rutella

Zavala

Danese

et al. 2005

The Journal of Immunology

201

154

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In recent years, several investigators have unraveled a previously unrecognized role for G-CSF in the regulation of T cell and dendritic cell functions. The experimental evidence in favor of G-CSF-mediated immune regulation includes the ability to switch T cell cytokine secretion profile to Th2 responses and the promotion of regulatory T cell and tolerogenic dendritic cell differentiation. Interestingly, G-CSF is beneficial in animals for the prevention and/or treatment of immune-mediated diseases, e.g., graft-vs-host disease, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and diabetes, suggesting a potential role in human autoimmune diseases. This review summarizes the growing body of evidence that supports a critical role for G-CSF as a novel mediator of T cell tolerance.

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Autoimmune Diabetes Is Suppressed by Transfer of Proinsulin-Encoding Gr-1+ Myeloid Progenitor Cells That Differentiate In Vivo Into Resting Dendritic Cells

Cited by 50 publications

References 48 publications

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

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

Granulocyte Colony-Stimulating Factor: A Novel Mediator of T Cell Tolerance

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