scholarly journals Mixed hematopoietic or T-cell chimerism above a minimal threshold restores perforin-dependent immune regulation in perforin-deficient mice

Blood ◽  
2013 ◽  
Vol 122 (15) ◽  
pp. 2618-2621 ◽  
Author(s):  
Catherine E. Terrell ◽  
Michael B. Jordan
Keyword(s):  
T Cell ◽  
Immune Regulation ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cd8 T Cell ◽  
Immune Dysregulation ◽  
Wild Type ◽  
Cell Engraftment ◽  
Key Points ◽  
Deficient Mice

Key Points Perforin deficiency causes immune dysregulation and hemophagocytic lymphohistiocytosis, which requires allogeneic HCT for long-term cure. In prf−/− mice, wild-type hematopoietic or CD8+ T-cell engraftment of only 10-20% is sufficient to reestablish normal immune regulation.

Excessive Anti-Viral CD8 T Cell Activation Inverts the IL-2 Consumptive Hierarchy Triggering Regulatory T Cell Collapse in Mouse Model for Hemophagocytic Lymphohistiocytosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1025-1025
Author(s):  
Stephanie Humblet-Baron ◽  
Dean Franckaert ◽  
Simon Bornschein ◽  
Bénédicte Cauwe ◽  
Susann Schonefeldt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Life Threatening ◽  
Deficient Mice

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8+ T cell activation. HLH occurs in both acquired and familial (FHL) forms, with mutations in Perforin being a common cause of FHL. In both conditions a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and life-threatening. Recent advances using experimental FHL triggered by lymphocytic choriomeningitis virus (LCMV) in Perforin-deficient mice have attributed the key distal event to be excessive IFNγ production, however the proximal events driving immune dysregulation have remained undefined. We investigated the role of regulatory T cells (Tregs) in the pathophysiology of experimental FHL. While we found no primary Treg defects in Perforin-deficient mice, Treg numbers collapsed following LCMV inoculation. The collapse of Treg numbers in LCMV-triggered Perforin-deficient, but not wildtype, mice was driven by the combination of lower IL-2 secretion by conventional CD4+ T cells, increased IL-2 consumption by activated CD8+ T cells and secretion of competitive sCD25 (IL-2 receptor). Together, these data demonstrate that excessive CD8+ T cell activation rewires the IL-2 homeostatic network away from Treg maintenance and towards feed-forward inflammation. In addition, reduced Treg number may contribute to the massive inflammation found in FHL. Disclosures No relevant conflicts of interest to declare.

CD19 as Foreign Antigen Elicits a Specific T-Cell Response and Mediates Rejection of High Grade B-Cell Lymphoma In Mice

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4907-4907
Author(s):  
Frank Lehmann ◽  
Armin Gerbitz ◽  
Christoph Loddenkemper ◽  
Elisabeth Kremmer ◽  
Josef Mautner ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Response ◽  
High Grade ◽  
Wild Type ◽  
Cell Compartment ◽  
Deficient Mice

Abstract Abstract 4907 Targeting selfantigens by specific T-cells for anti-tumor therapy bears the risk of fatal autoimmunity. Ideal self antigens are characterized by restricted expression in a specific cell compartment and are ideally highly expressed in malignant cells. Potential autoimmunity against those antigens must be tolerable for the host and loss of the expressing cell compartment has to be acceptable. In addition such self antigens should deliver survival signals for the tumor making escape variants highly unlikely or even impossible. The CD19 molecule as a member of the Ig superfamily is a transmembrane protein whose expression is restricted to B-cells in mouse and man. Aside from other proteins (CD81, CD21 etc.) it associates with the B-cell receptor (BCR) to augment its signal and appears to be of critical importance in the development and differentiation of B-cells. CD19 is expressed on virtually all B-cell malignancies and may provide a survival signal for at least some B cell malignancies. Targeting CD19 by antibodies appears to be effective in disease control making it an interesting target for T-cell therapy. We have developed a murine model for high grade B-cell lymphoma using lambda-human-cmyc transgenic mice. These animals spontaneously develop high grade B-cell lymphomas with similarities to human Burkittxs lymphoma. From these mice we established various cell lines which can be cultured long term and transferred onto recipients to form new locally or systemically growing lymphomas. Using homozygous CD19cre mice as a model for CD19 deficiency we show here that transfer of lethal doses of lymphoma cells (0.1-1.0 Mio 291cells) which form lymphomas in more than 90% of wild type recipients can be rejected long term (100 days) in up to 60% (9/14) of CD19 deficient mice (p=0.001, left figure). After s.c. injection 9/14 of CD19-/- animals transiently form tumors at the site of injection (right figure CD19-/-B6 rejection) which eventually disappear as a sign of rejection. STAT1-/- deficient animals served as a positive control since they harbour a NK- and T-cell defect. In case of outgrowing tumors (5/14), we still observe a strong infiltration by T-cells which is completely absent in wild type recipients. Heterotypic prime-boost-vaccination of CD19 deficient mice using a CD19 expression vector and long peptides results in a strong T-cell response as shown by IFNgamma ELISPOT and ELISA assay which is absent in wt mice or control vaccinated animals (chicken ovalbumine, OVA). Using peptide prediction several epitopes within the murine CD19 protein could be identified giving rise to mainly CD4 responses in the context of MHC H2b. Vaccination of CD19 deficient animals is being done to further improve survival of tumor-challenged animals. Collectively, our data indicate that CD19 serves as a rejection antigen in our model system and that protective T-cell responses can be generated to provide long survival after tumor challenge. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A role for CD9 molecules in T cell activation.

1996 ◽  
Vol 184 (2) ◽  
pp. 753-758 ◽  
Author(s):  
X G Tai ◽  
Y Yashiro ◽  
R Abe ◽  
K Toyooka ◽  
C R Wood ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Expression Cloning ◽  
Wild Type ◽  
Almost All ◽  
Antigen Presenting ◽  
Deficient Mice

Costimulation mediated by the CD28 molecule plays an important role in optimal activation of T cells. However, CD28-deficient mice can mount effective T cell-dependent immune responses, suggesting the existence of other costimulatory systems. In a search for other costimulatory molecules on T cells, we have developed a monoclonal antibody (mAb) that can costimulate T cells in the absence of antigen-presenting cells (APC). The molecule recognized by this mAb, 9D3, was found to be expressed on almost all mature T cells and to be a protein of approximately 24 kD molecular mass. By expression cloning, this molecule was identified as CD9, 9D3 (anti-CD9) synergized with suboptimal doses of anti-CD3 mAb in inducing proliferation by virgin T cells. Costimulation was induced by independent ligation of CD3 and CD9, suggesting that colocalization of these two molecules is not required for T cell activation. The costimulation by anti-CD9 was as potent as that by anti-CD28. Moreover, anti-CD9 costimulated in a CD28-independent way because anti-CD9 equally costimulated T cells from the CD28-deficient as well as wild-type mice. Thus, these results indicate that CD9 serves as a molecule on T cells that can deliver a potent CD28-independent costimulatory signal.

scholarly journals Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Adria Carbo ◽  
Danyvid Olivares-Villagómez ◽  
Raquel Hontecillas ◽  
Josep Bassaganya-Riera ◽  
Rupesh Chaturvedi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Wild Type ◽  
Content Type ◽  
Interleukin 21 ◽  
H Pylori ◽  
Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

EXTH-77. POLIO VIROTHERAPY OF MURINE BRAIN TUMORS INDUCES MICROGLIA PROLIFERATION AND INFLAMMATION THAT IS POTENTIATED BY IMMUNE CHECKPOINT BLOCKADE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi181-vi181
Author(s):  
Yuanfan Yang ◽  
Michael Brown ◽  
Kevin Stevenson ◽  
Giselle lopez ◽  
Reb Kornahrens ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Cd8 T Cell ◽  
Gene Set Enrichment Analysis ◽  
Type I ◽  
Acute Type ◽  
Type I Ifn ◽  
Term Survival

Abstract Immunotherapy with polio:rhinovirus recombinant (PVSRIPO) has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in durable radiographic responses and 21% long-term survival at 36 months. Ongoing research aims to enhance the clinical response rate by resolving the mechanisms of action and therapy resistance in vivo, thereby devising more effective therapies. Mouse glioma (CT2A) cells were intracranially implanted (day 0) in transgenic mice carrying poliovirus receptor CD155, and treated with intratumor PVSRIPO (5×105 pfu; day 6) to dissect early and late events following therapy. A blinded pathological review of 45 post-treatment tumors was performed. On day 8, a histological response, featured by tumor dissociation and shrinkage, with inflammation and microglia enrichment in the treated hemisphere, was common in PVSRIPO group (6/7) compared to controls (0/4). However, the response rate fell over time (7/12 on day 12; 1/7 on day 15) and the therapy was overcome by aggressive tumor regrowth. RNAseq was performed and Gene Set Enrichment Analysis of the tumor microenvironment revealed an acute type-I interferon (IFN)-related inflammation, correlating with the histological findings of profound proinflammatory engagement of microglia (Iba1+) widespread in the treated hemisphere. Microglia proliferation (Ki67+) was observed in the treated hemisphere, likely resulting from PVSRIPO infection, in CT2A and B16 intracranial models. This suggests an association of adaptive antitumor immunity—elicited by immediate intratumor type-I IFN-dominant inflammation—with tumor regression. Thus, buttressing type-I IFN directed antitumor CD8+T cell immunity, e.g. with blockade of the PD1:PD-L1 immune checkpoint, might contribute to tumor remission. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed longer median survival and higher long-term remission rate compared to monotherapy alone; CD8 T cell depletion can completely abrogate this efficacy with this therapy combination, confirming the role of anti-tumor immunity in this approach.

scholarly journals Factors Associated With CD8+ T-Cell Activation in HIV-1–Infected Patients on Long-term Antiretroviral Therapy

2014 ◽  
Vol 67 (2) ◽  
pp. 153-160 ◽  
Author(s):  
Lu Zheng ◽  
Babafemi Taiwo ◽  
Rajesh T. Gandhi ◽  
Peter W. Hunt ◽  
Ann C. Collier ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Factors Associated ◽  
Hiv 1
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