scholarly journals Truncation of C-mip (Tc-mip), a New Proximal Signaling Protein, Induces c-maf Th2 Transcription Factor and Cytoskeleton Reorganization

2003 ◽  
Vol 198 (5) ◽  
pp. 797-807 ◽  
Author(s):  
Philippe Grimbert ◽  
Asta Valanciute ◽  
Vincent Audard ◽  
André Pawlak ◽  
Sabine Le gouvelo ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Fetal Liver ◽  
Minimal Change Nephrotic Syndrome ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Ph Domain ◽  
Peripheral Blood Mononuclear ◽  
Proximal Signaling

Several arguments suggest that minimal change nephrotic syndrome (MCNS) results from yet unknown systemic disorder of T cell function. By screening a cDNA library from T cell relapse, we identified a new pleckstrin homology (PH) domain-containing protein encoded by a gene located on chromosome 16q24. Two alternative transcripts were identified. The first species (c-mip) was expressed in fetal liver, kidney, and peripheral blood mononuclear cells (PBMCs), but weakly detected in PBMCs from MCNS patients. The second form (Tc-mip, standing for truncated c-maf inducing protein), corresponds to subtracted transcript and lacks the NH2-terminal PH domain. The expression of Tc-mip was restricted to fetal liver, thymus, and MCNS PBMCs where it was specifically recruited in CD4+ T cells subset. Overexpression of Tc-mip in T cell Jurkat induced c-maf, transactivated the interleukin 4 gene and down-regulated the interferon γ expression, characteristic of a Th2 commitment. Moreover, the overexpression of Tc-mip induced Src phosphorylation, T cell clustering, and a cellular redistribution of the cytoskeleton-associated L-plastin, by a PI3 kinase independent pathway. Tc-mip represents therefore the first identified protein, which links proximal signaling to c-maf induction.

scholarly journals Targeted knockdown of Kv1.3 channels in T lymphocytes corrects the disease manifestations associated with systemic lupus erythematosus

2020 ◽  
Vol 6 (47) ◽  
pp. eabd1471 ◽  
Author(s):  
Marat Khodoun ◽  
Ameet A. Chimote ◽  
Farhan Z. Ilyas ◽  
Heather J. Duncan ◽  
Halima Moncrieffe ◽  
...  
Keyword(s):  
T Cell ◽  
Lupus Erythematosus ◽  
Healthy Donor ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Organ Damage ◽  
Interferon Γ ◽  
Peripheral Blood Mononuclear ◽  
Voltage Dependent

Lupus nephritis (LN) is an autoimmune disease with substantial morbidity/mortality and limited efficacy of available therapies. Memory T (Tm) lymphocytes infiltrate LN kidneys, contributing to organ damage. Analysis of LN, diabetic nephropathy, and healthy donor kidney biopsies revealed high infiltration of active CD8+ Tm cells expressing high voltage-dependent Kv1.3 potassium channels—key T cell function regulators—in LN. Nanoparticles that selectively down-regulate Kv1.3 in Tm cells (Kv1.3-NPs) reduced CD40L and interferon-γ (IFNγ) in Tm cells from LN patients in vitro. Kv1.3-NPs were tested in humanized LN mice obtained by engrafting peripheral blood mononuclear cells (PBMCs) from LN patients into immune-deficient mice. LN mice exhibited features of the disease: increased IFNγ and CD3+CD8+ T cell renal infiltration, and reduced survival versus healthy donor PBMC engrafted mice. Kv1.3-NP treatment of patient PBMCs before engraftment decreased CD40L/IFNγ and prolonged survival of LN mice. These data show the potential benefits of targeting Kv1.3 in LN.

scholarly journals CERI, CEFX, and CPI: Largely Improved Positive Controls for Testing Antigen-Specific T Cell Function in PBMC Compared to CEF

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 248
Author(s):  
Alexander A. Lehmann ◽  
Pedro A. Reche ◽  
Ting Zhang ◽  
Maneewan Suwansaard ◽  
Paul V. Lehmann
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Racial Bias ◽  
Immune Monitoring ◽  
Functional Fitness ◽  
Peripheral Blood Mononuclear ◽  
Cell Immunity ◽  
Antigen Presenting ◽  
Positive Controls

Monitoring antigen-specific T cell immunity relies on functional tests that require T cells and antigen presenting cells to be uncompromised. Drawing of blood, its storage and shipment from the clinical site to the test laboratory, and the subsequent isolation, cryopreservation and thawing of peripheral blood mononuclear cells (PBMCs) before the actual test is performed can introduce numerous variables that may jeopardize the results. Therefore, no T cell test is valid without assessing the functional fitness of the PBMC being utilized. This can only be accomplished through the inclusion of positive controls that actually evaluate the performance of the antigen-specific T cell and antigen presenting cell (APC) compartments. For Caucasians, CEF peptides have been commonly used to this extent. Moreover, CEF peptides only measure CD8 cell functionality. We introduce here universal CD8+ T cell positive controls without any racial bias, as well as positive controls for the CD4+ T cell and APC compartments. In summary, we offer new tools and strategies for the assessment of PBMC functional fitness required for reliable T cell immune monitoring.

scholarly journals Spontaneous secretion of interferon γ and interleukin 4 by human intraepithelial and lamina propria gut lymphocytes

Gut ◽  
1998 ◽  
Vol 42 (5) ◽  
pp. 643-649 ◽  
Author(s):  
M Carol ◽  
A Lambrechts ◽  
A Van Gossum ◽  
M Libin ◽  
M Goldman ◽  
...  
Keyword(s):  
Lamina Propria ◽  
Intestinal Mucosa ◽  
Mononuclear Cells ◽  
Critical Role ◽  
Gastrointestinal Diseases ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Peripheral Blood Mononuclear ◽  
Ifn Γ

Background—Cytokines secreted by intestinal T lymphocytes probably play a critical role in regulation of the gut associated immune responses.Aims—To quantify interferon γ (IFN-γ) and interleukin 4 (IL-4) secreting cells (SC) among human intraepithelial (IEL) and lamina propria (LPL) lymphocytes from the duodenum and right colon in non-pathological situations and in the absence of in vitro stimulation.Patients—Duodenal and right colonic biopsy specimens were obtained from patients with no inflammation of the intestinal mucosa.Methods—Intraepithelial and lamina propria cell suspensions were assayed for numbers of cells spontaneously secreting IFN-γ and IL-4 by a two site reverse enzyme linked immunospot technique (ELISPOT).Results—The relatively high proportion of duodenal lymphocytes spontaneously secreting IFN-γ (IEL 3.6%; LPL 1.9%) and IL-4 (IEL 1.3%; LPL 0.7%) contrasted with the very low numbers of spontaneously IFN-γ SC and the absence of spontaneously IL-4 SC among peripheral blood mononuclear cells. In the basal state, both IFN-γ and IL-4 were mainly produced by CD4+ cells. Within the colon, only 0.2% of IEL and LPL secreted IFN-γ in the basal state, and 0.1% secreted IL-4.Conclusions—Compared with peripheral lymphocytes substantial proportions of intestinal epithelial and lamina propria lymphocytes spontaneously secrete IFN-γ and/or IL-4. These cytokines are probably involved in the normal homoeostasis of the human intestinal mucosa. Disturbances in their secretion could play a role in the pathogenesis of gastrointestinal diseases.

BTK Inhibitors, Irrespective of ITK Inhibition, Increase Efficacy of a CD19/CD3 Bispecific Antibody in CLL

Blood ◽  
2021 ◽  
Author(s):  
Maissa Mhibik ◽  
Erika M. Gaglione ◽  
David Eik ◽  
Ellen K Kendall ◽  
Amy Blackburn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic Activity ◽  
Kinase Inhibitors ◽  
Bispecific Antibody ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Lymphocytic Leukemia ◽  
Peripheral Blood Mononuclear

Bruton Tyrosine Kinase inhibitors (BTKis) are a preferred treatment for patients with chronic lymphocytic leukemia (CLL). Indefinite therapy with BTKis, while effective, presents clinical challenges. Combination therapy can deepen responses, shorten treatment duration, and possibly prevent or overcome drug resistance. We previously reported on a CD19/CD3 bispecific antibody (bsAb) that recruits autologous T cell cytotoxicity against CLL cells in vitro. Compared to observations with samples from treatment-naïve patients, T cells from patients being treated with ibrutinib expanded more rapidly and exerted superior cytotoxic activity in response to the bsAb. In addition to BTK, ibrutinib also inhibits IL2 inducible T cell Kinase (ITK). In contrast, acalabrutinib, does not inhibit ITK. Whether ITK inhibition contributes to the observed immune effects is unknown. To better understand how BTKis modulate T-cell function and cytotoxic activity, we cultured peripheral blood mononuclear cells (PBMCs) from BTKi-naive, and ibrutinib- or acalabrutinib-treated CLL patients with CD19/CD3 bsAb in vitro. T-cell expansion, activation, differentiation, and cytotoxicity were increased in PBMCs from patients on treatment with either BTKi compared to that observed for BKTi-naïve patients. BTKi therapy transcriptionally downregulated immunosuppressive effectors expressed by CLL cells, including CTLA-4 and CD200. CTLA-4 blockade with ipilimumab in vitro increased the cytotoxic activity of the bsAb in BTKi-naïve but not BTKi-treated PBMCS. Taken together, BTKis enhance bsAb induced cytotoxicity by relieving T cells of immunosuppressive restraints imposed by CLL cells. The benefit of combining bsAb immunotherapy with BTKis needs to be confirmed in clinical trials.

Effect of pazopanib on myeloid-derived suppressor cells and T-cell function in patients with metastatic renal cell carcinoma.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 455-455
Author(s):  
Kiranpreet K. Khurana ◽  
Pat A. Rayman ◽  
Paul Elson ◽  
Brian I. Rini ◽  
James Finke
Keyword(s):  
T Cell ◽  
Interferon Gamma ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
T Cell Function ◽  
Pre Treatment ◽  
Over Time

455 Background: Tyrosine kinase inhibitors have been shown to have an effect on T cell function. Sunitinib decreases immunosuppression in patients with metastatic renal cell carcinoma (mRCC) as seen by a reduction in myeloid derived suppressor cells (MDSC) that inhibit T cell function. The effect of pazopanib on immune function is unknown. Methods: Peripheral blood mononuclear cells from 21 patients with mRCC treated with pazopanib were thawed for cycle 1 day 1, cycle 1 day 28, cycle 2 day 28, and cycle 4 day 28. Total MDSC and neutrophilic, monocytic, and lineage-negative MDSC subsets were measured by flow cytometry. T cell response was measured by interferon-gamma production after in vitro stimulation by anti-CD3/anti-CD28 beads. Pre-treatment cycle 1 day 1 levels were compared to cycle 4 day 28. Results: In mRCC patients, MDSCs comprise 4.7 % (median, range 1.7-32.9 %) of the peripheral blood mononuclear cells pre-treatment. Neutrophilic MDSC subset is the most prevalent at 2.0 % (median, range 0.3-30.4 %). Monocytic MDSCs comprise 1.5 % (median, range 0.4-5.3 %), and lineage-negative MDSCs comprise only 0.15 % (median, range 0.01-1.03 %). We found that pazopanib does not significantly decrease the percentage of MDSCs (total or subpopulations) over time with the exception of a modest decrease in the lineage-negative MDSC subset (p = 0.08). In terms of T cell function, pre-treatment level of CD3+ interferon-gamma was found to be 10.6 % (median, range 1.3-22.3 %). In contrast, pazopanib significantly increased CD3+ interferon-gamma level over time to 18.1 % (median, range 3.0-25.0 %), p = 0.03. Conclusions: Our study shows that pazopanib does not significantly reduce MDSC levels in patients with mRCC. However, pazopanib improves T cell function over time, as seen by a significant increase in CD3+ interferon-gamma production.

scholarly journals Gene expression of T lymphocytes of gravid cows during preimplantation

2013 ◽  
Vol 82 (2) ◽  
pp. 131-134 ◽  
Author(s):  
Yousuke Maeda ◽  
Kana Yamamoto ◽  
Hiromichi Ohtsuka ◽  
Takaaki Ando ◽  
Michiko Tomioka ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Γδ T Cells ◽  
Interferon Γ ◽  
T Cell Subsets ◽  
Interleukin 4 ◽  
Blocking Factor

An interaction between the conceptus and the immune system of animals is important during implantation. The aim of this study was to clarify the gene expression of T cell subsets in gravid cows during the preimplantation period. Peripheral blood from 14 Holstein dairy cows was taken 14 days after artificial insemination. Based on the gravidity, cows were divided into gravid (n = 8) and nongravid (n = 6) groups. Mononuclear cells from peripheral blood were stimulated with phytohaemagglutinin and then CD4+, CD8+, and WC1+ γδ T cell subsets were isolated using magnetic cell sorting. The expression of interferon γ, interleukin 4, and progesterone induced blocking factor were determined using real-time PCR. The expression of interleukin 4 and progesterone induced blocking factor was significantly higher in WC1+ γδ T cells from gravid cows. In addition, interleukin 4 expression in WC1+ γδ T cells from gravid cows was significantly higher than that in CD4+ and CD8+ T cells. This study describes for the first time the important role of WC1+ γδ T cells during the preimplantation period in cows.

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