PERIPHERAL TOLERANCE INDUCTION BY LYMPH NODE STROMA

2008 ◽  
pp. 113-127 ◽  
Author(s):  
Erika D. Reynoso ◽  
Je-Wook Lee ◽  
Shannon J. Turley*
Keyword(s):  
Lymph Node ◽  
Tolerance Induction ◽  
Peripheral Tolerance

scholarly journals CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells

2002 ◽  
Vol 197 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Melanie S. Vacchio ◽  
Richard J. Hodes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tolerance Induction ◽  
Peripheral Tolerance ◽  
Cd8 Cells ◽  
Costimulatory Signal ◽  
Cd28 Costimulation

Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y–specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y–specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells.

scholarly journals Prevention of Peripheral Tolerance by a Dendritic Cell Growth Factor: Flt3 Ligand as an Adjuvant

1998 ◽  
Vol 188 (11) ◽  
pp. 2075-2082 ◽  
Author(s):  
Bali Pulendran ◽  
J.L. Smith ◽  
M. Jenkins ◽  
M. Schoenborn ◽  
E. Maraskovsky ◽  
...  
Keyword(s):  
Tolerance Induction ◽  
Cd40 Ligand ◽  
Peripheral Tolerance ◽  
Clinical Settings ◽  
Flt3 Ligand ◽  
Systemic Injection ◽  
Large Numbers ◽  
Factor Α ◽  
Antigen Presenting

Injections of soluble proteins are poorly immunogenic, and often elicit antigen-specific tolerance. The mechanism of this phenomenon has been an enduring puzzle, but it has been speculated that tolerance induction may be due to antigen presentation by poorly stimulatory, resting B cells, which lack specific immunoglobulin receptors for the protein. In contrast, adjuvants, or infectious agents, which cause the release of proinflammatory cytokines such as tumor necrosis factor α and interleukin 1β in vivo are believed to recruit and activate professional antigen-presenting cells to the site(s) of infection, thereby eliciting immunity. Here we show that administration of Flt3 ligand (FL), a cytokine capable of inducing large numbers of dendritic cells (DCs) in vivo, (a) dramatically enhances the sensitivity of antigen-specific B and T cell responses to systemic injection of a soluble protein, through a CD40–CD40 ligand–dependent mechanism; (b) influences the class of antibody produced; and (c) enables productive immune responses to otherwise tolerogenic protocols. These data support the hypothesis that the delicate balance between immunity and tolerance in vivo is pivotally controlled by DCs, and underscore the potential of FL as a vaccine adjuvant for immunotherapy in infectious disease and other clinical settings.

NKT Cells in the Liver are Important for Peripheral Tolerance Induction

2018 ◽  
Vol 102 ◽  
pp. S694
Author(s):  
Wei Li ◽  
Zhuonan Li ◽  
Zhanpeng Wang ◽  
Hongyu Liu ◽  
Lianbo Zhang ◽  
...  
Keyword(s):  
Tolerance Induction ◽  
Nkt Cells ◽  
Peripheral Tolerance

scholarly journals Cyclosporin A-Induced Autoimmunity in the Rat: Central versus Peripheral Tolerance

2002 ◽  
Vol 15 (2) ◽  
pp. 81-87 ◽  
Author(s):  
J.G.M.C. Damoiseaux
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cyclosporin A ◽  
Tolerance Induction ◽  
Chronic Phase ◽  
Metastatic Breast ◽  
Autologous Bone Marrow ◽  
Peripheral Tolerance ◽  
Central Tolerance ◽  
Total Body

Cyclosporin A-induced autoimmunity (CsA-AI) is a thymus dependent and T cell-mediated autoimmune disease that is readily induced in rodents (1, 2) and also occurs in humans (3). Induction of CsA-AI requires total body X-irradiation, rescue with syngeneic or autologous bone marrow, and subsequent cyclosporin A (CsA) administration for about 4 weeks (4). Because the induction protocol involves bone marrow transplantation (BMT), CsA-AI is also referred to as syngeneic or autoimmune graft-versus-host disease (GvHD) (5). The CsA-AI model is being studied for three reasons. Firstly, the animal model, and in particular the chronic phase of the disease, has been reported to have several macroscopic and histopathologic similarities with human scleroderma (6,7). Secondly, CsA-AI is clinically and experimentally examined for its graft- versus-tumour potential against lympho-hematopoietic malignancies as well as metastatic breast cancer (8). And thirdly, CsA-AI has been very informative in terms of T cell development and tolerance induction, including central as well as peripheral control of autoreactivity (9, 10). In the present review, a summary of the characteristics of CsA-AI will be given. Next, the supposed mechanism of CsA for interference with central tolerance induction will be presented. Finally, the role of peripheral tolerance, and in particular dominant T cell tolerance as mediated by regulatory T cells, will be discussed in relation to induction of CsA-AI as well as to strain-related resistance to CsA-AI.

scholarly journals Human Lymph Node Stromal Cells Have the Machinery to Regulate Peripheral Tolerance during Health and Rheumatoid Arthritis

2020 ◽  
Vol 21 (16) ◽  
pp. 5713
Author(s):  
Janine S. Hähnlein ◽  
Reza Nadafi ◽  
Tineke A. de Jong ◽  
Johanna F. Semmelink ◽  
Ester B. M. Remmerswaal ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Lymph Node ◽  
Antigen Presentation ◽  
Stromal Cells ◽  
Immune Modulation ◽  
Ex Vivo ◽  
Human Leukocyte ◽  
Interferon Γ ◽  
Peripheral Tolerance ◽  
Lymph Node Stromal Cells

Background: In rheumatoid arthritis (RA) the cause for loss of tolerance and anti-citrullinated protein antibody (ACPA) production remains unidentified. Mouse studies showed that lymph node stromal cells (LNSCs) maintain peripheral tolerance through presentation of peripheral tissue antigens (PTAs). We hypothesize that dysregulation of peripheral tolerance mechanisms in human LNSCs might underlie pathogenesis of RA. Method: Lymph node (LN) needle biopsies were obtained from 24 RA patients, 23 individuals positive for RA-associated autoantibodies but without clinical disease (RA-risk individuals), and 14 seronegative healthy individuals. Ex vivo human LNs from non-RA individuals were used to directly analyze stromal cells. Molecules involved in antigen presentation and immune modulation were measured in LNSCs upon interferon γ (IFNγ) stimulation (n = 15). Results: Citrullinated targets of ACPAs were detected in human LN tissue and in cultured LNSCs. Human LNSCs express several PTAs, transcription factors autoimmune regulator (AIRE) and deformed epidermal autoregulatory factor 1 (DEAF1), and molecules involved in citrullination, antigen presentation, and immunomodulation. Overall, no clear differences between donor groups were observed with exception of a slightly lower induction of human leukocyte antigen-DR (HLA-DR) and programmed cell death 1 ligand (PD-L1) molecules in LNSCs from RA patients. Conclusion: Human LNSCs have the machinery to regulate peripheral tolerance making them an attractive target to exploit in tolerance induction and maintenance.

Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo

Immunity ◽  
1994 ◽  
Vol 1 (4) ◽  
pp. 327-339 ◽  
Author(s):  
Elizabeth R. Kearney ◽  
Kathryn A. Pape ◽  
Dennis Y. Loh ◽  
Marc K. Jenkins
Keyword(s):  
T Cell ◽  
Tolerance Induction ◽  
Peripheral Tolerance ◽  
T Cell Immunity ◽  
Cell Immunity

scholarly journals Viral and Bacterial Infections Interfere with Peripheral Tolerance Induction and Activate CD8+ T Cells to Cause Immunopathology

1998 ◽  
Vol 187 (5) ◽  
pp. 763-774 ◽  
Author(s):  
Stephan Ehl ◽  
Joachim Hombach ◽  
Peter Aichele ◽  
Thomas Rülicke ◽  
Bernhard Odermatt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Cd8 T Cells ◽  
Bacterial Infections ◽  
Tolerance Induction ◽  
Cytolytic Activity ◽  
Peripheral Tolerance ◽  
Infectious Agents ◽  
The Impact

We studied the impact of various infectious and proinflammatory agents on the induction of peripheral T cell tolerance. Adoptive transfer of CD8+ T cells from lymphocytic choriomeningitis virus (LCMV) T cell receptor transgenic mice into LCMV antigen transgenic mice expressing the LCMV glycoprotein epitope (gp) 33–41 under control of a major histocompatibility complex class I promoter led to efficient induction of peripheral tolerance after a period of transient activation. If, however, the recipient mice were challenged with viral or bacterial infections or proinflammatory agents (lipopolysaccharide or Poly:IC) early after cell transfer, tolerance induction was prevented and instead, CD8+ T cell activation leading to vigorous expansion and generation of cytolytic activity ensued. This became manifest in significant immunopathology mainly involving destruction of the splenic architecture and lysis of antigen-expressing lymphocyte and macrophage populations. Important parameters involved in the activation of host-reactive T cells by nonspecific infectious agents included the presence, localization, and quantity of the specific transgene-encoded self-antigen; in contrast, CD4+ T cells were not required. In mice surviving the acute phase, the transferred CD8+ T cells persisted at high levels in an anergic state; they were unable to generate cytolytic activity in vitro or to control LCMV infection in vivo. These results impinge on our understanding of the role of infectious agents in graft verus host reactions towards minor histocompatibility antigens.

scholarly journals Tolerogenic transcriptome landscape in CD8+ T lymphocytes after exposure to erythrocyte-targeted antigens

2018 ◽  
Author(s):  
Alizée J. Grimm ◽  
Cédric Gobet ◽  
Giacomo Diaceri ◽  
Xavier Quaglia-Thermes ◽  
Jeffrey A. Hubbell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Tolerance Induction ◽  
Peripheral Tolerance ◽  
Response To Treatment ◽  
Gene Expression Response ◽  
Genes Encoding ◽  
Expression Response ◽  
T Cell Phenotypes

AbstractOur group has recently shown induction of antigen-specific T cell tolerance through targeting of the antigen to erythrocytes in situ. The tolerogenic state is characterized by initial proliferation of antigen-specific T cells and subsequent acquisition of signatures associated with both deletional, anergic and regulatory T cell phenotypes. In this study we wished to further understand the molecular mechanisms behind induction of tolerance by erythrocyte-targeted antigens. RNA sequencing was performed to determine how gene expression response is regulated in tolerized ovalbumin-specific CD8+ T cells and which molecular pathways are activated after treatment with this technology. Treatment with erythrocyte-targeted antigens led to the upregulation of genes encoding several TCR co-inhibitory receptors such as CTLA4, PD1, LAG3, TIGIT and CD200R1, and lack of upregulation of cytotoxic and pro-inflammatory signaling molecule genes. Modulation in expression of the master transcription factors Egr2/NFatc1, Nur77 family and E2f1 was also observed, all known to be associated with the natural process of establishment of peripheral tolerance. Expression of these genes differed in response to treatment with soluble ovalbumin or SIINFEKL MHCI peptide, suggesting a specific mechanism of T cell modulation and tolerance induction in response to the erythrocyte-associated forms.

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