scholarly journals CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes

2017 ◽  
Vol 114 (6) ◽  
pp. E980-E989 ◽  
Author(s):  
Yvonne M. C. Kooy-Winkelaar ◽  
Dagmar Bouwer ◽  
George M. C. Janssen ◽  
Allan Thompson ◽  
Martijn H. Brugman ◽  
...  
Keyword(s):  
T Cells ◽  
Celiac Disease ◽  
T Cell ◽  
Nk Cell ◽  
Intraepithelial Lymphocytes ◽  
Duodenal Biopsy ◽  
Mucosal Inflammation ◽  
Current Evidence ◽  
Biopsy Specimens ◽  
Hla Dq2

Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin−IELs) in the duodenum. In ∼50% of patients with RCDII, these Lin−IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant Lin−IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2–restricted gluten-specific CD4+ T cells. We now show that gluten-specific CD4+ T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin−IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4+ T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-xL. Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4+ T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin−IELs and CD3−CD56+ IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4+ T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation.

scholarly journals Thymic origin of embryonic intestinal gamma/delta T cells.

1993 ◽  
Vol 177 (2) ◽  
pp. 257-263 ◽  
Author(s):  
D Dunon ◽  
M D Cooper ◽  
B A Imhof
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Cell Subpopulation ◽  
Current Evidence ◽  
Gamma Delta T Cells ◽  
Intestinal Colonization ◽  
Gamma Delta ◽  
Embryo Cells

Current evidence suggests both thymic and extrathymic origins for T cells. Studies in mice favor an in situ origin for a prominent population of intestinal intraepithelial lymphocytes that express gamma/delta T cell receptor (TCR). This developmental issue is explored in an avian model in which the gamma/delta lymphocytes constitute a major T cell subpopulation that is accessible for study during the earliest stages of lymphocyte development. In the chick embryo, cells bearing the gamma/delta TCR appear first in the thymus where they reach peak levels on days 14-15 of embryogenesis, just 2 d before gamma/delta T cells appear in the intestine. Using two congenic chick strains, one of which expresses the ov antigen, we studied the origin and kinetics of intestinal colonization by gamma/delta T cells. The embryonic gamma/delta+ thymocytes homed to the intestine where they survived for months, whereas an embryonic gamma/delta- thymocyte population enriched in thymocyte precursors failed to give rise to intestinal gamma/delta+ T cells. Embryonic hemopoietic tissues, bone marrow, and spleen, were also ineffective sources for intestinal gamma/delta+ T cells. Intestinal colonization by gamma/delta+ thymocytes occurred in two discrete waves in embryos and newly hatched birds. The data indicate that intestinal gamma/delta T cells in the chicken are primarily thymic migrants that are relatively long-lived.

scholarly journals Anti-Transglutaminase Antibody Assay of the Culture Medium of Intestinal Biopsy Specimens Can Improve the Accuracy of Celiac Disease Diagnosis

2006 ◽  
Vol 52 (6) ◽  
pp. 1175-1180 ◽  
Author(s):  
Antonio Carroccio ◽  
Lidia Di Prima ◽  
Giuseppe Pirrone ◽  
Calogero Scalici ◽  
Ada M Florena ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Diagnostic Accuracy ◽  
Culture Medium ◽  
Villous Atrophy ◽  
Disease Diagnosis ◽  
Intraepithelial Lymphocytes ◽  
Duodenal Biopsy ◽  
Intestinal Biopsy ◽  
Serum Antibodies ◽  
Biopsy Specimens

Abstract Background: We measured anti-transglutaminase (anti-tTG) antibody in the culture medium of intestinal biopsy specimens from patients with suspected celiac disease (CD) and evaluated the relationship between antibody production and severity of intestinal mucosal damage. Methods: We performed diagnostic testing for CD on 273 consecutive patients. In addition to routine histologic evaluation of duodenal biopsy specimens, we assayed anti-tTG antibodies in serum and in the culture medium of duodenal biopsy specimens. Results: CD was diagnosed in 191 of the 273 patients. Sensitivity and specificity of the serum anti-endomysium (EmA) and anti-tTG assays were 83% and 85% and 99% and 95%, respectively, and both had 88% diagnostic accuracy. EmA and anti-tTG assayed in the culture medium had 98% sensitivity, 100% specificity, and 98% diagnostic accuracy (vs serum assays; P <0.0001). Twenty-nine CD patient specimens (16%) were negative for serum anti-tTG and EmA; for 24 of these patients, anti-tTG assay of the culture medium was positive. The CD patients whose biopsy specimens were positive for serum antibodies showed the following intestinal histologies: total villous atrophy, 35%; severe villous atrophy, 25%; mild atrophy, 25%; villi with no atrophy but with increased intraepithelial lymphocytes, 15%. None of the CD patients whose specimens were negative for serum antibodies showed total or severe villous atrophy; 77% had mild villous atrophy, and 23% had no villous atrophy but had increased intraepithelial lymphocyte counts. Mild villous atrophy was also seen in specimens from ∼15% of patients without CD. Conclusion: Anti-tTG assay of the culture medium of biopsy specimens can improve the accuracy of CD diagnosis in patients negative for serum antibodies.

scholarly journals Anti-tumor effects of RTX-240: an engineered red blood cell expressing 4-1BB ligand and interleukin-15

2021 ◽  
Author(s):  
Shannon L. McArdel ◽  
Anne-Sophie Dugast ◽  
Maegan E. Hoover ◽  
Arjun Bollampalli ◽  
Enping Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Cell ◽  
Nk Cells ◽  
Red Blood Cell ◽  
Safety Profile ◽  
Nk Cell ◽  
Cell Activity ◽  
In Vivo Studies

AbstractRecombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.

scholarly journals Evidence for the divergence of innate and adaptive T-cell precursors before commitment to the αβ and γδ lineages

Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6591-6600 ◽  
Author(s):  
Jan Kisielow ◽  
Luigi Tortola ◽  
Jacqueline Weber ◽  
Klaus Karjalainen ◽  
Manfred Kopf
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Negative Selection ◽  
Intraepithelial Lymphocytes ◽  
Lineage Commitment ◽  
Γδt Cells ◽  
Cell Lineages ◽  
Innate T Cells ◽  
Tcr Signals

Abstract In addition to adaptive T cells, the thymus supports the development of unconventional T cells such as natural killer T (NKT) and CD8αα intraepithelial lymphocytes (IELs), which have innate functional properties, particular antigenic specificities, and tissue localization. Both conventional and innate T cells are believed to develop from common precursors undergoing instructive, TCR-mediated lineage fate decisions, but innate T cells are proposed to undergo positive instead of negative selection in response to agonistic TCR signals. In the present study, we show that, in contrast to conventional αβT cells, innate αβT cells are not selected against functional TCRγ rearrangements and express TCRγ mRNA. Likewise, in contrast to the majority of γδT cells, thymic innate γδT cells are not efficiently selected against functional TCRβ chains. In precursors of conventional T cells, autonomous TCR signals emanating from the pre-TCR or γδTCR in the absence of ligand mediate selection against the TCR of the opposite isotype and αβ/γδ lineage commitment. Our data suggest that developing innate T cells ignore such signals and rely solely on agonistic TCR interactions. Consistently, most innate T cells reacted strongly against autologous thymocytes. These results suggest that innate and adaptive T-cell lineages do not develop from the same pool of precursors and potentially diverge before αβ/γδ lineage commitment.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals Pathogenic T Cells in Celiac Disease Change Phenotype on Gluten Challenge: Implications for T‐Cell‐Directed Therapies

2021 ◽  
pp. 2102778
Author(s):  
Asbjørn Christophersen ◽  
Stephanie Zühlke ◽  
Eivind G. Lund ◽  
Omri Snir ◽  
Shiva Dahal‐Koirala ◽  
...  
Keyword(s):  
T Cells ◽  
Celiac Disease ◽  
T Cell

scholarly journals Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+T Cells

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Abena K. R. Kwaa ◽  
Chloe A. G. Talana ◽  
Joel N. Blankson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Effector Cell ◽  
Cell Function ◽  
Nk Cell ◽  
Suppressive Capacity ◽  
Short Course ◽  
Shock And Kill ◽  
Hiv 1

ABSTRACTCurrent shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+T cell and natural killer (NK) cell responses. In this study, we tested the hypothesis that alpha interferon (IFN-α) could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-α treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors. Furthermore, IFN-α enhanced global CP CD8+T cell cytokine responses and the suppressive capacity of ES CD8+T cells. Our data suggest that IFN-α treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.IMPORTANCEData suggest that HIV+individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest since they complement the function of CD8+T cells. Here, we demonstrate the ability of short-course alpha interferon (IFN-α) treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+T cell function. These results point to the possibility of exploring such short-course IFN-α treatments for the enhancement of effector cell function in HIV+patients in future cure strategies.

scholarly journals Hydroa Vacciniforme and Hydroa Vacciniforme-Like Lymphoproliferative Disorder: A Spectrum of Disease Phenotypes Associated with Ultraviolet Irradiation and Chronic Epstein–Barr Virus Infection

2020 ◽  
Vol 21 (23) ◽  
pp. 9314
Author(s):  
Chien-Chin Chen ◽  
Kung-Chao Chang ◽  
L Jeffrey Medeiros ◽  
Julia Yu-Yun Lee
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
Ultraviolet Irradiation ◽  
Epstein Barr Virus ◽  
Nk Cell ◽  
Current Evidence ◽  
Barr Virus ◽  
Ebv Infection ◽  
Hydroa Vacciniforme ◽  
Epstein Barr

Hydroa vacciniforme (HV) is a rare form of photosensitivity disorder in children and is frequently associated with Epstein–Barr virus (EBV) infection, whereas HV-like lymphoproliferative disorders (HVLPD) describe a spectrum of EBV-associated T-cell or natural killer (NK)-cell lymphoproliferations with HV-like cutaneous manifestations, including EBV-positive HV, atypical HV, and HV-like lymphoma. Classic HV occurs in childhood with papulovesicules on sun-exposed areas, which is usually induced by sunlight and ultraviolet irradiation, and mostly resolves by early adult life. Unlike classic HV, atypical or severe HV manifests itself as recurrent papulovesicular eruptions in sun-exposed and sun-protected areas associated occasionally with facial edema, fever, lymphadenopathy, oculomucosal lesions, gastrointestinal involvement, and hepatosplenomegaly. Notably, atypical or severe HV may progress to EBV-associated systemic T-cell or natural killer (NK)-cell lymphoma after a chronic course. Although rare in the United States and Europe, atypical or severe HV and HV-like lymphoma are predominantly reported in children from Asia and Latin America with high EBV DNA levels, low numbers of NK cells, and T cell clones in the blood. In comparison with the conservative treatment used for patients with classic HV, systemic therapy such as immunomodulatory agents is recommended as the first-line therapy for patients with atypical or severe HV. This review aims to provide an integrated overview of current evidence and knowledge of HV and HVLPD to elucidate the pathophysiology, practical issues, environmental factors, and the impact of EBV infection.

scholarly journals Peripheral Blood Immunological Features Associated with Aortic Valve Disease and Ascending Throcic Aorta Aneurysm and Dilation

2015 ◽  
Vol 3 (1) ◽  
pp. 11-20
Author(s):  
Kaushal Kishore Tiwari ◽  
Silverio Sbrana ◽  
Stefano Bevilacqua ◽  
Paola Giungato ◽  
Angela Pucci ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Aortic Valve ◽  
Peripheral Blood ◽  
Chemokine Receptors ◽  
Aortic Valve Disease ◽  
Nk Cell ◽  
Valve Disease ◽  
T Cell Subsets ◽  
Group A

INTRODUCTION: Ascending thoracic aortic aneurysm (TAA) is a multi-factorial process in which histological modifications and immune-mediated inflammation are closely associated. The predominant role of a Th1-mediated response in influencing aortic wall remodeling, dilation, and aneurysm formation has been suggested by previous studies. Recently, the importance of chemokine receptors for Th1 cells recruitment into vascular inflammatory sites, as well as of the balance between pro- and anti-inflammatory T-cell subsets in influencing the severity of coronary artery disease, have been described.MATERIAL AND METHODS: We evaluated activation markers and chemokine receptors expression on peripheral T-cell and NK cell subsets of subject with aortic valve disease associated with ascending TAA (ascending aortic diameter > 4 cm) and undergoing elective surgery for TAA (Group A), in comparison with patients with aortic valve disease without TAA (ascending aortic diameter < 4 cm) (Group B). Peripheral blood samples from the two groups were also compared for intracellular T-lymphocyte cytokine production, frequency of regulatory T cells (Treg) and soluble levels of cytokine and chemokines. The aortic size index (ASI) was considered a parameter able to reflect aortic pathophysiological modifications leading to aortic dilation.RESULTS: The results demonstrated correlations between ASI values and CCR5 expression on CD3+, CD3+/CD8+, CD4+ and CD4+/CD28- T-cell subsets. In Group A the expression of CCR5 was higher on CD3+/CD8+, CD4+ and CD4+/CD28- T-cell subsets, when compared with Group B. CD4+ and CD4+/CD28- T-cells in Group A showed also a higher expression for the co-stimulatory molecule CD28 and the activation marker CD25, respectively. An increased expression of CXCR3 was found on CD4+, CD3+/CD8+ and CD3+/TCR+ T-cell subsets in Group A. A higher circulating fraction of NK cells, together with a higher NK cell positivity for CX3CR1, were observed in aneurysmatic patients. Intracellular cytokine analysis demonstrated a higher fraction of CD3+/CD4+ T-cells producing IL-17A and IL-10 in Group A, together with a higher intracellular content for IL-21. Finally, a higher soluble level of fractalkine (CX3CL1) has been detected in aneurysm group.CONCLUSION: Results indicate a higher activation state, migratory capacity and cytotoxic potential of peripheral blood NK and T-cell subsets in patients with aortic valve disease associated with ascending TAA, when compared with patients affected by aortic valve disease alone. These findings, together with the observed higher polarization towards a Th17 in patients with aortic aneurysm could suggest the involvement of autoimmune mechanisms leading to cellular loss, inflammation and fibrosis during ascending aortic wall dilation and aneurysmatic progression.Journal of Universal College of Medical Sciences Vol. 3, No. 1, 2015: 11-20

Characterization of HLH-Like Manifestations as a CRS Variant in Patients Receiving CD22 CAR T-Cells

Blood ◽  
2021 ◽  
Author(s):  
Daniel A Lichtenstein ◽  
Fiorella Schischlik ◽  
Lipei Shao ◽  
Seth M Steinberg ◽  
Bonnie Yates ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Nk Cell ◽  
Severe Neutropenia ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
T Cell Expansion

CAR T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T-cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Amongst 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase and occasionally hemophagocytosis. Development of carHLH was associated with pre-infusion NK-cell lymphopenia and higher bone marrow T/NK-cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK-cell lymphopenia amplified pre-infusion differences in those with carHLH without evidence for defects in NK-cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.

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