scholarly journals Differential Outcome of Tolerance Induction in Naive versus Activated Theiler's Virus Epitope-Specific CD8+ Cytotoxic T Cells

2007 ◽  
Vol 81 (12) ◽  
pp. 6584-6593 ◽  
Author(s):  
Meghann Teague Getts ◽  
Byung S. Kim ◽  
Stephen D. Miller
Keyword(s):  
T Cells ◽  
Demyelinating Disease ◽  
Cytotoxic T Lymphocyte ◽  
Cytotoxic T Cells ◽  
Disease Model ◽  
Tolerance Induction ◽  
Virus Clearance ◽  
Fatal Reaction ◽  
Virus Epitope ◽  
Antigen Presenting

ABSTRACT Tolerance induced by the intravenous injection of peptide-pulsed, ethylene carbodiimide (ECDI)-fixed splenic antigen-presenting cells (Ag-SP) is a safe and effective method of inducing specific unresponsiveness in CD4+ T cells for the prevention and treatment of a variety of autoimmune diseases. We determined whether Ag-SP tolerance could also be used to tolerize CD8+ T cells. We show in the Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease model of multiple sclerosis that CD8+ T cells specific for both dominant and subdominant epitopes can be rendered tolerant. Interestingly, although virus clearance was delayed, lack of the virus-specific cytotoxic T-lymphocyte response did not result in the conversion of normally TMEV-resistant C57BL/6 mice to a susceptible phenotype. Importantly, we found that Ag-SP tolerance may not be a practical treatment for human diseases in which CD8+ T cells play a major role in pathogenesis, as tolerance induction in mice previously infected with TMEV led to a severe, often fatal reaction.

scholarly journals Liver-Derived Dendritic Cells Induce Donor-Specific Hyporesponsiveness: Use of Sponge Implant as a Cell Transplant Model

2001 ◽  
Vol 10 (3) ◽  
pp. 343-350 ◽  
Author(s):  
Yang-Jen Chiang ◽  
Lina Lu ◽  
John J. Fung ◽  
Shiguang Qian
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mouse Liver ◽  
Cytotoxic T Lymphocyte ◽  
Tolerance Induction ◽  
Cell Transplant ◽  
Spleen Cells ◽  
Infiltrating Cells ◽  
Transplant Model ◽  
Ctl Activity

Spontaneously accepted mouse liver allografts are capable of protecting subsequently transplanted donor organs from rejection; however, the underlying mechanisms are unclear. Dendritic cells (DC) residing in liver grafts are likely important in tolerance induction. DC propagated from mouse liver with GM-CSF are phenotypically and functionally immature. They are poor allostimulators in MLR and prolong survival of pancreatic islet allografts. It has been problematic to perform mechanistic studies in an islet transplant model because of difficulties in obtaining sufficient graft infiltrating cells. In this study, we used a sponge allograft model [i.e., a subcutaneously implanted sponge matrix loaded with B10 (H2b) spleen cells]. To investigate the influence of administration of donor (B10) liver-derived DC on alloimmune reactivity of C3H (H2k) hosts, sponge graft infiltrating cells (SGIC) and recipient spleen cells were isolated, and their immunopheno-type and donor-specific cytotoxic T lymphocyte (CTL) activity were examined. The results illustrate that donor-specific CTL activity of T cells are lower in recipients that had received systemic treatment with liver-derived immature DC, associated with a decrease in CD8+ cell population and an increase in Gr-1+ cells in SGIC, compared with recipients treated with mature bone marrow (BM)-derived DC. Interestingly, administration of liver DC directly into the sponge did not inhibit T cell responses. These data suggest that systemic administration of donor liver DC induces donor-specific hyporesponsiveness, probably not by direct inhibition of graft infiltrating T cells. The increased Gr-1+ cells may play immune regulatory roles in induction of host donor-specific hyporesponsiveness.

scholarly journals Role of Antigen-Presenting Cells in Mediating Tolerance and Autoimmunity

1999 ◽  
Vol 191 (11) ◽  
pp. 2021-2028 ◽  
Author(s):  
Kristine M. Garza ◽  
Steven M. Chan ◽  
Rakesh Suri ◽  
Linh T. Nguyen ◽  
Bernhard Odermatt ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Islet Cells ◽  
Antigen Presenting Cells ◽  
Cell Receptor ◽  
Lymphocytic Choriomeningitis ◽  
Activation Markers ◽  
Insulin Promoter ◽  
Lymphocyte Activity ◽  
Antigen Presenting

The mechanisms that determine whether receptor stimulation leads to lymphocyte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic β-islet cells together with T cells expressing an LCMV-gp–specific T cell receptor to assess the requirements for the induction of autoimmunity. Our studies have shown that administration of the gp peptide gp33 leads to the activation of P14-transgenic T cells, as measured by the upregulation of activation markers and the induction of effector cytotoxic activity. This treatment also leads to expansion and deletion of P14 T cells. Despite the induction of cytotoxic T lymphocyte activity, peptide administration is not sufficient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These findings suggest that the induction of tolerance versus autoimmunity is determined by resting versus activated antigen-presenting cells.

scholarly journals Allorestricted cytotoxic T cells. Large numbers of allo-H-2Kb-restricted antihapten and antiviral cytotoxic T cell populations clonally develop in vitro from murine splenic precursor T cells.

1985 ◽  
Vol 162 (2) ◽  
pp. 592-606 ◽  
Author(s):  
J Reimann ◽  
D Kabelitz ◽  
K Heeg ◽  
H Wagner
Keyword(s):  
T Cells ◽  
High Probability ◽  
Cytotoxic T Lymphocyte ◽  
Cytotoxic T Cells ◽  
Large Fraction ◽  
Cytotoxic T Cell ◽  
Wild Type ◽  
Large Numbers ◽  
Simplex Virus

Cytotoxic T lymphocyte (CTL) responses of splenic T cells from C57BL/6 B6) mice and mutant H-2Kbm1 (bm1) mice to haptenic (trinitrophenyl [TNP] ) and herpes simplex virus (HSV) determinants in the context of an allogenic (wild-type or mutant) H-2Kb molecule were analyzed in a modified limiting dilution system. In the B6-anti-bm1TNP mixed leukocyte reaction (MLR), estimated frequencies for precursors of CTL clones that lysed bm1TNP targets ranged from 1/120 to 1/400; in the bm1-anti-B6TNP MLR, estimated frequencies of precursors of CTL clones that lysed B6TNP targets ranged from 1/500 to 1/1,300. Estimated frequencies for precursors of CTL clones that lysed the respective unmodified and TNP-modified allogeneic targets were two- to three-fold lower. Lytic specificity patterns determined by split-well analysis showed that at least 20-30% of the generated CTL populations (selected for a high probability of clonality) in both MLR displayed allorestricted lysis of TNP-modified concanavalin A blast targets. In the B6-anti-bm1HSV MLR, estimated frequencies for precursors of CTL clones that lysed bm1HSV targets ranged from 1/70 to 1/300; in the bm1-anti-B6HSV MLR, estimated frequencies for precursors of CTL clones that lysed B6HSV targets ranged from 1/300 to 1/1,200. Again, estimated frequencies for precursors of CTL clones that lysed the respective noninfected and virus-infected allogeneic targets were two- to fourfold lower. Of the CTL populations selected for a high probability of clonality at least 30-60% displayed allorestricted lysis of virus-infected lipopolysaccharide blast targets in both MLR. It is concluded that a large fraction of clonally developing CTL populations stimulated with TNP-modified or HSV-infected allo-H-2Kb-bearing cells displayed an allorestricted pattern of recognition. It was further evident that the estimated frequencies of splenic precursors that generated allorestricted CTL clones was two- to threefold higher than the estimated frequencies of precursors that gave rise to the respective alloreactive CTL populations.

scholarly journals Cholangiocarcinoma with respect to IgG4 Reaction

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Kenichi Harada ◽  
Yasuni Nakanuma
Keyword(s):  
T Cells ◽  
Plasma Cells ◽  
Cytotoxic T Cells ◽  
Immune Surveillance ◽  
Intraepithelial Neoplasia ◽  
Cell Switching ◽  
Igg4 Related Disease ◽  
Regulatory Cytokine ◽  
High Risk Factor ◽  
Antigen Presenting

IgG4 reactions marked by infiltration of IgG4-positive plasma cells in affected organs occur in cancer patients and in patients with IgG4-related diseases. Extrahepatic cholangiocarcinomas including gall bladder cancer are often accompanied by significant IgG4 reactions; these reactions show a negative correlation with CD8-positive cytotoxic T cells, suggesting that the evasion of immune surveillance is associated with cytotoxic T cells. The regulatory cytokine IL-10 may induce IgG4-positive plasma cell differentiation or promote B cell switching to IgG4 in the presence of IL-4. Cholangiocarcinoma cells may function as nonprofessional antigen presenting cells that indirectly induce IgG4 reactions via the IL-10-producing cells and/or these may act as Foxp3-positive and IL-10-producing cells that directly induce IgG4 reactions. Moreover, IgG4-related disease is a high-risk factor for cancer development; IgG4-related sclerosing cholangitis (IgG4-SC) cases associated with cholangiocarcinoma or its precursor lesion biliary intraepithelial neoplasia (BilIN) have been reported. IgG4-positive cell infiltration is an important finding of IgG4-SC but is not a histological hallmark of IgG4-SC. For the diagnosis of IgG4-SC, its differentiation from cholangiocarcinoma remains important.

scholarly journals Interleukin-2 Family Members and their Role in Demyelinating Disease

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
: Mahendra K Bhopale
Keyword(s):  
T Cells ◽  
Demyelinating Disease ◽  
Cytotoxic T Cells ◽  
Interleukin 2 ◽  
Th2 Cells ◽  
T Helper ◽  
Th1 Cell ◽  
Memory Cd8 T Cells ◽  
Regulatory Effects ◽  
Negative Regulatory Role

Interleukin-2 (IL-2) has a family which includes IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines. This family group of an IL-2 cytokine plays important, but different roles in neurologically related demyelinating disease studied in multiple sclerosis (MS) and it’s experimentally induced rodent models. IL-2 play role in strong T-cell expansion and participates in the maintenance of T-regs cells, but also keep in the stimulation and proliferation of pathogenic T cells. IL-4 induces differentiation of naïve helper T cells (Th0) to Th2 cells. IL-7 promotes Th1 cell differentiation. IL-9 is a hematopoietic growth factor for major pathogenic Th17 cells in EAE. IL-15 is necessary for memory CD8+ T cells and plays a negative regulatory role through CD8+ CD122+ T cells in reducing Th17-mediated inflammation. IL-21 has potent regulatory effects on the natural killer (NK) cells and cytotoxic T cells. IL-21 activates CD4+ and up-regulates the Th2 and Th17 subsets of T helper cells. Based on different roles of each family member in demyelinating disease, bio-agents and therapeutic agents have been attempted in an experimental model to study their role in demyelinating disease is described in the present review.

scholarly journals Cd8− T Cell Transfectants That Express a High Affinity T Cell Receptor Exhibit Enhanced Peptide-Dependent Activation

2001 ◽  
Vol 194 (8) ◽  
pp. 1043-1052 ◽  
Author(s):  
Phillip D. Holler ◽  
Alice R. Lim ◽  
Bryan K. Cho ◽  
Laurie A. Rund ◽  
David M. Kranz
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cytotoxic T Lymphocyte ◽  
Cell Activity ◽  
Cell Receptor ◽  
Wild Type ◽  
High Affinity ◽  
Antigen Presenting

T cells are activated by binding of the T cell receptor (TCR) to a peptide-major histocompatibility complex (MHC) complex (pMHC) expressed on the surface of antigen presenting cells. Various models have predicted that activation is limited to a narrow window of affinities (or dissociation rates) for the TCR–pMHC interaction and that above or below this window, T cells will fail to undergo activation. However, to date there have not been TCRs with sufficiently high affinities in order to test this hypothesis. In this report we examined the activity of a CD8-negative T cell line transfected with a high affinity mutant TCR (KD = 10 nM) derived from cytotoxic T lymphocyte clone 2C by in vitro engineering. The results show that despite a 300-fold higher affinity and a 45-fold longer off-rate compared with the wild-type TCR, T cells that expressed the mutant TCRs were activated by peptide. In fact, activation could be detected at significantly lower peptide concentrations than with T cells that expressed the wild-type TCR. Furthermore, binding and functional analyses of a panel of peptide variants suggested that pMHC stability could account for apparent discrepancies between TCR affinity and T cell activity observed in several prior studies.

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