The Role of B Lymphocytes as Key Antigen-Presenting Cells in the Development of T Cell-Mediated Autoimmune Type 1 Diabetes

2002 ◽  
pp. 212-227 ◽  
Author(s):  
D.V. Serreze ◽  
P.A. Silveira
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
B Lymphocytes ◽  
Antigen Presenting Cells ◽  
Antigen Presenting

Abstract 252: Interleukin-27 Signaling Regulates Myeloid Cells Activation in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Iuliia Peshkova ◽  
Aliia Fatkhullina ◽  
Ekaterina Koltsova
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Antigen Presenting Cells ◽  
Atherosclerotic Lesions ◽  
Mediators Of Inflammation ◽  
Antigen Presenting ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

Atherosclerosis is a lipid-driven inflammatory disease characterized by the progressive plaque growth in the vessels. Cytokines are important mediators of inflammation and atherosclerosis. While pro-inflammatory cytokines were extensively investigated, little is known about the role of anti-inflammatory cytokines as to their ability to control vascular inflammation. We tested whether immunoregulatory IL-27R signaling is important to control inflammation in mouse models of atherosclerosis. We found that atherosclerosis-prone mice with hematopoietic deficiency of IL-27R ( Ldlr -/- mice reconstituted with bone marrow from Il27ra -/- ) or global deficiency ( Il27ra -/- x Apoe -/- ) developed significantly larger atherosclerotic lesions compared to controls. Atherosclerotic lesions in IL-27R deficient mice contained more CD45 + leukocytes and CD4 + T cells, which produced pro-atherogenic cytokines IL-17A and TNF-α. These cytokines normally suppressed by IL-27, regulated the expression of CCL2 and other chemokines, which in turn led to accumulation of myeloid CD11b + and CD11c + cells in atherosclerotic aortas. Using two-photon microscopy, we found enhanced interactions between antigen presenting cells and T cells in the aortas of IL-27R deficient mice accompanied by enhanced CD4 T cell proliferation. Moreover, macrophages in Il27ra -/- aortas also demonstrated enhanced ability to produce pro-inflammatory cytokines, including IL-1. The blockade of IL-1R signaling, however, strongly suppressed atherosclerosis progression in IL-27R deficient but not control mice, suggesting an important role of IL-27 in the regulation of IL-1 production in atherosclerosis. Overall, our data demonstrate that IL-27R signaling in atherosclerosis is required to control function of antigen presenting cells modulating subsequent T cell activation in the aortas. Moreover, it controls macrophage activation and pro-inflammatory myeloid cell-derived cytokine production. These mechanisms altogether curb pathogenic T cell lineage differentiation and, thus, atherosclerosis, suggesting potent anti-atherogenic role of IL-27.

scholarly journals Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell-Mediated Regulation and Type 1 Diabetes Development in NOD Mice

Diabetes ◽  
2006 ◽  
Vol 55 (7) ◽  
pp. 2098-2105 ◽  
Author(s):  
P. Alard ◽  
J. N. Manirarora ◽  
S. A. Parnell ◽  
J. L. Hudkins ◽  
S. L. Clark ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Function ◽  
Nod Mice ◽  
Antigen Presenting Cell ◽  
Diabetes Development ◽  
Antigen Presenting

The role of antigen-presenting cells in the regulation of allergen-specific T cell responses

1998 ◽  
Vol 10 (6) ◽  
pp. 607-613 ◽  
Author(s):  
Martien L Kapsenberg ◽  
Catherien MU Hilkens ◽  
Eddy A Wierenga ◽  
Pawel Kalinski
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Cell Responses ◽  
Antigen Presenting

A Crucial Role for Antigen Presenting Cells in Donor CD4+CD25+ Regulatory T Cell Mediated Suppression of Experimental Gvhd.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 688-688
Author(s):  
Isao Tawara ◽  
Tomomi Toubai ◽  
Chelsea Malter ◽  
Yaping Sun ◽  
Evelyn Nieves ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Conflicts Of Interest ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Indoleamine 2 ◽  
Effector Phase ◽  
Antigen Presenting

Abstract Abstract 688 Several lines of evidence show that donor derived mature CD4+CD25+Foxp3+ regulatory T cells (Tregs) suppress experimental GVHD. The mechanism of GVHD suppression by donor Tregs is, however, not well understood. Recent observations have brought in a renewed focus on the role of professional antigen presenting cells (APCs) in the induction and maintenance of GVHD by alloreactive T cell effectors (Teffs). But the role of APCs in modulating the responses of Tregs after allogeneic BMT is not known. We first tested the requirement of host APCs in Treg mediated regulation of GVHD. We utilized a clinically relevant CD8+ T cell dependent MHC matched but miHA disparate C3H.SW (H-2b) → wild type (wt) or Class II deficient Abb (II-/-) B6 (H-2b) model of GVHD because host APCs and target tissues from the Abb animals do not express class II and as such donor CD4+CD25+ Tregs will not directly interact with the host tissues while alloreactive CD8+ T cells could still respond to miHA allo-antigens presented by the intact class I on host APCs. The recipient Abb (II-/-) and wt B6 animals were lethally irradiated and transplanted with 2 × 105 CD8+ T cells along with or without CD4+CD25+ Tregs at 1:2 ratio from either syngeneic B6 or allogeneic C3H.SW animals. The wt recipients that received Tregs showed significantly better survival compared with the wt animals that did not receive any Tregs (P< 0.01) while the class II-/- animals showed similar GVHD mortality regardless of Treg infusion (P>0.8). To confirm whether the lack of Treg mediated protection was only due to the absence of interaction with host type APCs and also to exclude the possibility of development of Tregs from the infused BM we thymectomized wt B6 animals and then generated [B6 B6] controls and the [Abb B6] chimeras. These chimeric animals were used as recipients in a second BMT and transplanted with CD8+ Teffs and Tregs from allogeneic C3H.SW mice. Tregs reduced GVHD mortality in the [B6 B6] (P<0.01) but not in the [Abb B6] animals (P>0.7). We next evaluated whether host APC expression of allo-antigens alone was sufficient for Treg mediated GVHD protection in the absence of class II expression on target tissues by generating [B6 B6] and [B6 Abb] chimeras and found that Tregs demonstrated equivalent GVHD protection even when the class II allo-antigens were expressed only on the host APCs. Mechanistic studies demonstrated that Tregs significantly inhibited the expansion of CD8+ Teffs on days +10 and 17 after BMT in the spleens of the WT recipients (P<0.05) but not in the class II-/- animals. However, infused Tregs demonstrated reduced expansion in the class II-/- animals only early after BMT (on day +10) but was equivalent at later time-point (days 17 and 29) to the WT recipients. We further determined the mechanisms by which host APCs might contribute to Treg mediated protection. To this end we used IL-10-/-, indoleamine 2, 3 dioxygenase (IDO)-/- deficient animals and generated [IL-10-/- B6] and [IDO-/- B6] animals as recipients. Tregs mitigated GVHD mortality regardless of the ability of the host APCs to express IL-10 or IDO. We next determined whether Tregs suppressed Teffs in their activation phase at the level of their interaction with host APCs or in the effector phase. C3H.SW CD8+ T cells were primed (both in vivo and ex vivo with B6 allo-antigens) and then infused into the [β2mg-/- B6] animals such that pre-activated CD8 Teffs would still be able to initiate GVHD without the need for host APCs for their activation. Infusion of donor Tregs into [β2mg-/- B6] animals that were transplanted with the pre-activated Teffs mitigated GVHD severity demonstrating that Tregs, once activated by host APCs, were capable of suppressing Teff cells in their effector phase. Collectively our data show (a) host APCs are critical (b) expression of allo-antigens on host target tissues is not obligatory (c) host derived IL-10 and IDO are not critical for Treg mediated GVHD protection and (d) Tregs can mitigate GVHD by suppressing alloreactive Teffs in the effector phase even after they have been activated. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Juxtaposition of Coeliac Disease and Type 1 Diabetes; the Role of Shared Non-Human Leukocyte Antigen Loci

2018 ◽  
Vol 3 (1) ◽  
pp. 1-8
Author(s):  
Iraj Shahramian ◽  
Hossein Shahdadi ◽  
Ali Bazi ◽  
Nosratollah Masinaeinejad ◽  
Mojtaba Delaramnasab
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
Coeliac Disease ◽  
Adaptor Protein ◽  
Human Leukocyte ◽  
Substantial Impact ◽  
Leukocyte Antigen

Although extensive studies have been performed to explore the role of various alleles within the human leukocyte antigen (HLA) in susceptibility to coeliac disease (CD) and type 1 diabetes (T1D), less attention has been dedicated to the role of shred non-HLA loci. In present report, we have provided a review on the role of genetic variants in seven shared non-HLA loci in determination the risk of either CD or T1D. The literature search was done on the Web of Knowledge, PubMed, and Scopus databases using keywords of polymorphism, coeliac disease, and type 1 diabetes. The literature published within 2000-2017 were recruited. Seven discussed shared loci between CD and T1D were those resided within cytotoxic T-lymphocyte associated protein 4 (CTL4), regulator of G protein signaling (RGS1), SH2B adaptor protein (SH2B3), T cell activation Rho GTPase activating protein (TAGAP), interleukin 18 receptor accessory protein (IL18RAP), protein tyrosine phosphatase, non-receptor type (PTPN2), and C-C motif chemokine receptor (CCR5). Interaction between polymorphisms of these genes seems to exert a substantial impact on determination the risk of CD and T1D in context of each other. Polymorphisms residing in these loci can exert synergistic or opposing effects toward either protection or predisposition to CD and T1D. The majority of these polymorphisms affect the function of cytokine signaling or T cell activating pathways. The net outcome deems to be delineated by a complex interaction between these adaptor arms, as well as the modulatory effects of other components of immune system, in particular HLA alleles.

scholarly journals IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Huang ◽  
Qiyuan Tan ◽  
Ningwen Tai ◽  
James Alexander Pearson ◽  
Yangyang Li ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Gut Microbiota ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Treg Cells ◽  
Diabetes Development

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

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