scholarly journals Leptin: A Critical Regulator of CD4+ T-cell Polarization in Vitro and in Vivo

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 56-62 ◽  
Author(s):  
Arvind Batra ◽  
Besir Okur ◽  
Rainer Glauben ◽  
Ulrike Erben ◽  
Jakob Ihbe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Polarization ◽  
Th2 Cells ◽  
Regulatory Function ◽  
Wild Type ◽  
T Helper ◽  
T Cell Polarization

Abstract Besides being mandatory in the metabolic system, adipokines like leptin directly affect immunity. Leptin was found to be necessary in T helper 1 (Th1)-dependent inflammatory processes, whereas effects on Th2 cells are rarely understood. Here, we focused on leptin in T-helper cell polarization and in Th2-mediated intestinal inflammation in vivo. The induction of cytokine-producing Th1 or Th2 cells from naive CD4+ T cells under polarizing conditions in vitro was generally decreased in cells from leptin-deficient ob/ob mice compared with wild-type mice. To explore the in vivo relevance of leptin in Th2-mediated inflammation, the model of oxazolone-induced colitis was employed in wild-type, ob/ob, and leptin-reconstituted ob/ob mice. Ob/ob mice were protected, whereas wild-type and leptin-reconstituted ob/ob mice developed colitis. The disease severity went in parallel with local production of the Th2 cytokine IL-13. A possible explanation for the protection of ob/ob mice in Th1- as well as in Th2-dependent inflammation is provided by a decreased expression of the key transcription factors for Th1 and Th2 polarization, T-bet and GATA-3, in naive ob/ob T cells. In conclusion, these results support the regulatory function of the adipokine leptin within T-cell polarization and thus in the acquired immune system and support the concept that there is a close interaction with the endocrine system.

scholarly journals Rapid Development of Th2 Activity During T Cell Priming

2003 ◽  
Vol 10 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Adam F. Cunningham ◽  
Kai-Michael Toellner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rapid Development ◽  
Critical Role ◽  
Cell Polarization ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Th 1 ◽  
Th1 And Th2

The paradigm of T helper-1 (Th-1) and Th-2 cells developing from non-committed naïve precursors is firmly established. Th1 cells are characterized by IFN production and, in mice, the selective switching to IgG2a. Conversely IL-4 production and selective switching to IgG1 and IgE characterize Th2 cells. Analysis of Th2 inductionin vitroindicates that this polarization develops gradually in T cells activated by anti-CD3 in the presence of IL-4; conversely anti-CD3 and IFN induce Th1 cells. In this report, we explore evidence that indicates that the T helper cell polarizationin vivocannot solely be explained by the cytokine environment. This is provided by studying the early acquisition of Th1 and Th2 activities during responses to a mixture of Th1 and Th2-inducing antigens. It is shown that these divergent forms of T cell help can rapidly develop in cells within a single lymph node. It is argued that early polarization to show Th-1 or Th-2 behavior can be induced by signals delivered during cognate interaction between virgin T cells and dendritic cells, in the absence of type 1 or type 2 cytokines. This contrasts with the critical role of the cytokines in reinforcing the Th-phenotype and selectively expanding T helper clones.

scholarly journals Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

1994 ◽  
Vol 179 (4) ◽  
pp. 1273-1283 ◽  
Author(s):  
R Manetti ◽  
F Gerosa ◽  
M G Giudizi ◽  
R Biagiotti ◽  
P Parronchi ◽  
...  
Keyword(s):  
T Cells ◽  
Interferon Gamma ◽  
Specific Antigen ◽  
Th2 Cells ◽  
Interleukin 12 ◽  
T Helper ◽  
Ifn Gamma ◽  
Selection Of

Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.

scholarly journals T-cell–intrinsic Tif1α/Trim24 regulates IL-1R expression on TH2 cells and TH2 cell-mediated airway allergy

2016 ◽  
Vol 113 (5) ◽  
pp. E568-E576 ◽  
Author(s):  
Jimena Perez-Lloret ◽  
Isobel S. Okoye ◽  
Riccardo Guidi ◽  
Yashaswini Kannan ◽  
Stephanie M. Coomes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Allergic Diseases ◽  
Treg Cells ◽  
Th2 Cells ◽  
T Helper 2 ◽  
Cytokines And Chemokines ◽  
Th2 Cell

There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αβ+CD4+ T-helper 2 (TH2) cells orchestrate the type-2–driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081–E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4gfp+αβ+CD4+ TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell–intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24−/− T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1–regulated signaling. Following this prediction, we found that Trim24−/− T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1β–mediated activation in vitro and in vivo, and fail to respond to IL-1β–exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell–intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.

scholarly journals The Decreased Replicative Capacity of Simian Immunodeficiency Virus SIVmac239Δnef Is Manifest in Cultures of Immature Dendritic Cells and T Cells

2000 ◽  
Vol 74 (5) ◽  
pp. 2406-2413 ◽  
Author(s):  
Davorka Messmer ◽  
Ralf Ignatius ◽  
Christine Santisteban ◽  
Ralph M. Steinman ◽  
Melissa Pope
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Culture System ◽  
Wild Type ◽  
Virus Dose ◽  
Immunodeficiency Virus

ABSTRACT Transmission of simian immunodeficiency virus SIVmac239Δnef (Δnef) to macaques results in attenuated replication of the virus in most animals and ultimately induces protection against challenge with some pathogenic, wild-type SIV strains. It has been difficult, however, to identify a culture system in which the replication of Δnef is severely reduced relative to that of the wild type. We have utilized a primary culture system consisting of blood-derived dendritic cells (DCs) and autologous T cells. When the DCs were fully differentiated or mature, the DC–CD4+ T-cell mixtures supported replication of both the parental SIV strain, 239 (the wild type), and its mutant withnef deleted (Δnef), irrespective of virus dose and the cell type introducing the virus to the coculture. In contrast, when immature DCs were exposed to Δnef and cocultured with T cells, virus replication was significantly lower than that of the wild type. Activation of the cultures with a superantigen allowed both Δnef and the wild type to replicate comparably in immature DC–T-cell cultures. Immature DCs, which, it has been hypothesized, capture and transmit SIV in vivo, are deficient in supporting replication of Δnef in vitro and may contribute to the reduced pathogenicity of Δnef in vivo.

scholarly journals Mutational Analysis of Superantigen Activity Responsible for the Induction of Skin Erythema by Streptococcal Pyrogenic Exotoxin C

1998 ◽  
Vol 66 (10) ◽  
pp. 5020-5026 ◽  
Author(s):  
Junichi Yamaoka ◽  
Eijiro Nakamura ◽  
Yoshifumi Takeda ◽  
Sadao Imamura ◽  
Nagahiro Minato
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mutational Analysis ◽  
Wild Type ◽  
Stimulatory Activity ◽  
Fold Reduction ◽  
Skin Erythema ◽  
Dose Dependent Fashion

ABSTRACT Streptococcal pyrogenic exotoxin C (SPEC), when injected intradermally, induces erythema in unsensitized rabbits. In the present study, we examined whether this erythema induction is due to the T-cell stimulatory activity of SPEC as a superantigen. Analysis by using single-residue mutant SPECs indicated that mutant SPECs Y15I, A16E, and Y17I, in which tyrosine 15, alanine 16, and tyrosine 17 were replaced with isoleucine, glutamic acid, and isoleucine, respectively, exhibited significantly reduced mitogenic activity for Vβ2+ human T cells in vitro, and Y15I showed as much as a 1,000-fold reduction. Y15I mutant SPEC, however, retained the ability to bind to major histocompatibility complex class II antigen and to form a homodimer, implying that residue 15 is critically important for the interaction of SPEC with T-cell antigen receptor β chains. When injected intradermally into normal rabbits, wild-type SPEC induced a characteristic erythema after 3 h in a dose-dependent fashion, which was associated with polymorphonuclear and mononuclear cell infiltration. This erythema formation was found to be severely suppressed by systemic pretreatment with cyclosporin A, suggesting the involvement of host T cells. Y15I mutant SPEC exhibited nearly 1,000-fold less erythema induction in vivo than wild-type SPEC. Altogether, the present results strongly suggest that erythema induction in rabbits by SPEC is attributable mostly to its T-cell stimulatory activity as a superantigen.

scholarly journals Interleukin-23 deficiency alters thymic selection in lupus-prone mice

Lupus ◽  
2019 ◽  
Vol 28 (8) ◽  
pp. 1007-1012
Author(s):  
H Dai ◽  
V C Kyttaris
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Polarization ◽  
Lymphoid Organs ◽  
Thymic Selection ◽  
Wild Type ◽  
Thymic Development ◽  
T Cell Polarization ◽  
Interleukin 23 ◽  
Secondary Lymphoid Organs

We have previously reported that IL-23 receptor deficiency in MRL. lpr mice ameliorates lupus by altering the balance of pro- and anti-inflammatory cytokines in secondary lymphoid organs. As IL-23 may also impact thymic selection, we evaluated the effect of IL-23 on thymic T cell development in lupus-prone mice. We generated IL-23p19-deficient MRL. lpr mice and harvested their thymus at 8 weeks of age. We found that the late stage double negative DN4 population was increased in IL-23p19–/– MRL. lpr mice when compared to IL-23p19+/+ MRL. lpr mice. Despite this, mature thymocytes (CD24–TCRβ+) were decreased by more than 50% in the IL-23p19-deficient mice versus wild-type controls. This was associated with a decrease in the generation of CD8+ T cells, possibly through downregulation of the IL-7 receptor. CD8+ T cells were not only fewer in numbers but also had decreased expression of the migration-related receptors CD44 and CD62L in the thymus and spleens of IL-23p19-deficient versus wild-type mice. We propose that IL-23 promotes the development of lupus-like autoimmunity not only through T cell polarization and cytokine production in the peripheral lymphoid organs but also by influencing T cell thymic development.

Blocking the regulatory T cell molecule LAG-3 augments in vivo anti-tumor immunity in an autochthonous model of prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2573-2573
Author(s):  
C. G. Drake ◽  
C. Kelleher ◽  
T. Bruno ◽  
T. Harris ◽  
D. Flies ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Specific Antigen ◽  
Cell Activity ◽  
Cd8 T Cell ◽  
Regulatory Function

2573 Background: LAG-3 is a CD4 homolog expressed on activated T cells, NK cells, tumor infiltrating lymphocytes (TIL), and plasmacytoid dendritic cells. Recently, we showed that LAG-3 was relatively overexpressed in specific T cells rendered unresponsive in vivo by the presence of cognate self-antigen. These anergic T cells display regulatory function both in vitro and in vivo, and blockade of LAG-3 with a non-depleting monoclonal antibody significantly mitigates their regulatory T cell activity. Methods: Using a novel model of prostate cancer in which a tumor-specific antigen is expressed in autochthonous tumors, we tested whether treatment with a non-depleting anti-LAG-3 antibody affected trafficking and function of tumor-specific T cells. Results: LAG-3 blockade significantly augments specific CD8 T cell trafficking to antigen-expressing tumors, but not to normal tissue. Most significantly, LAG-3 blockade functionally reversed CD8 T cell tolerance as assayed by an in vivo cytotoxic T lymphocyte (CTL) assay. Combining LAG-3 blockade with specific anti-tumor vaccination results in a dramatic increase in activated CD8 T cells in the tumor parenchyma. Conclusions: Taken together, these data support the concept that treatment with a LAG-3 blocking antibody may significantly delay disease progression in patients with cancer. We have recently generated a panel of monoclonal antibodies directed against human LAG-3; several of these antibodies significantly augment human T cell responses in vitro. No significant financial relationships to disclose.

Interrogating resistance mechanisms to PD-1 blockade therapy with CRISPR.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3077-3077
Author(s):  
Davis Yuri Torrejon ◽  
Jesse Meir Zaretsky ◽  
Daniel Sanghoon Shin ◽  
Mykola Onyshchenko ◽  
Gabriel Abril-Rodriguez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Cell Line ◽  
Wild Type ◽  
Antitumor Effects ◽  
Ifn Gamma ◽  
Syngeneic Mouse Model

3077 Background: We tested the biological significance of the loss of function (LOF) mutations in JAK1 or JAK2 within the IFN-receptor-pathway and in beta-2-microglobulin (B2M), which had been found in patient biopsies with resistance to anti-PD-1 therapy. Methods: We used CRISPR/Cas9 genome editing to generate JAK1, JAK2 and B2M knockout (KO) sublines of HLA-A*02:01 MART-1 or NY-ESO-1 positive human melanoma cell lines, tested using in-vitro T cell co-culture systems and in a syngeneic mouse model (MC38) to analyze the in-vivo antitumor activity with anti-PD1 therapy. Results: The JAK2-KO cell line was insensitive to IFN-gamma induced signaling and growth arrest (p < 0.001 compared with IFN-alpha or beta), while the JAK1-KO cell line was insensitive to all three IFNs. Baseline MHC class I expression after JAK1-KO was unaffected (baseline-MFI 1230 JAK1-KO vs 1570 parental, p = 0.66), but the magnitude of change was lower upon IFN-gamma exposure compared to the parental (MFI change with IFN-gamma, 26% decrease for JAK1-KO vs 50% increase for parental). There was no difference in in-vitro cytotoxicity by NY-ESO-1-TCR transgenic T-cells against JAK1-KO-NY-ESO-1+ melanoma cells compared to the parental (78% vs 82% cytotoxicity at 10:1 E:T ratio, p NS). However, B2M-KO was resistant to killing by MART-1 specific T-cells (2% vs 96% cytotoxicity at 10:1 E:T ratio, p < 0.0001). On the other hand, in the MC38 model the significant antitumor activity of anti-PD-1 against the wild type cells was lost in both JAK2-KO and B2M-KO. The percentage of CD8+ T cells has a trend of increase with anti-PD1 compared to untreated in the MC38 wild type (p = 0.1 d12), and a trend of decrease in MC38 B2M-KO (p = 0.2 d12), but no change in JAK2-KO tumors (p = 0.7 d12). Conclusions: JAK1/2 LOF mutations result in insensitivity to IFN induced antitumor effects, but does not impair T cell recognition and cytotoxicity, while B2M LOF results in lack of antigen presentation to T cells and loss of antitumor activity. However both lead to in-vivo resistance to anti-PD-1 therapy, suggesting they do so by independent mechanisms.

Histone Deacetylase Inhibitors Induce Immuno-Dominant Suppression of Dendritic Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 456-456 ◽  
Author(s):  
Pavan Reddy ◽  
Yoshinobu Maeda ◽  
Raimon Duran-Struuck ◽  
Oleg Krijanovski ◽  
Charles Dinarello ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Hdac Inhibitors ◽  
Class Ii ◽  
Wild Type ◽  
Tnf Α

Abstract We and others have recently demonstrated that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor with anti-neoplastic properties, reduces experimental acute graft-versus-host disease (GVHD). We have now investigated the mechanisms of action of two HDAC inhibitors, SAHA and ITF 2357, on allogeneic immune responses. Bone marrow derived dendritic cells (DCs) were preincubated with the HDAC inhibitors at nanomolar concentrations for 16–18 hours and stimulated with lipopolysaccharide (LPS). Pretreatment of DCs caused a significant reduction in the secretion of TNF-α, IL-12p70 and IL-6 compared to the untreated controls (P< 0.005). Similar effects were seen using human peripheral blood mononuclear cell derived DCs. Pre-treatment of both murine and human DCs also significantly reduced their in vitro stimulation of allogeneic T cells as measured by proliferation and IFN-γ production (P<0.01). We determined the in vivo relevance of these observations utilizing a mouse model where the responses of allogeneic donor bm12 T cells depended on the function of injected host B6 DCs would stimulate. Recipient Class-II −/− B6 (H-2b) received 11 Gy on day -1 and were injected with 4–5 x 106 wild type B6 DCs treated with SAHA or with media on days -1 and 0 and then transplanted with 2 x 106 T cells and 5 x 106 TCDBM cells from either syngeneic B6 or allogeneic bm12 donors. SAHA treatment of DCs significantly reduced expansion of allogeneic donor CD4+ T cells on day +7 after BMT compared to controls (P<0.05). SAHA treatment induced a similarly significant reduction in the expansion of CD8+ cells in Class I disparate [bm1→β2M−/−] model. In vitro, SAHA treatment significantly suppressed the expression of CD40 and CD80 but did not alter MHC class II expression. Surprisingly, when mixed with normal DCs at 1:1 ratio, SAHA treated DCs dominantly suppressed allogeneic T cell responses. The regulation of T cell proliferation was not reversible by addition of IL-12, TNF-α, IL-18, anti-IL-10 or anti-TGFβ, either alone or in combination. Suppression of allogeneic responses was contact dependent in trans-well experiments. To address whether the regulation of SAHA treated DCs required contact with T cells, we devised a three cell experiment where SAHA treated DCs lacked the capacity to present antigens to T cells. DCs from B6 MHC Class II deficient (H-2b) were treated with SAHA and co-cultured with wild type B6 (H-2b) DCs along with purified allogeneic BALB/c (H-2d) CD4+ T cells in an MLR. Allogeneic CD4+ T cells proliferated well, demonstrating the regulation to be dependent on contact between SAHA treated DCs and T cells. To address the in vivo relevance of this suppression, we utilized a well characterized [BALB/c →B6] mouse model of acute GVHD. Recipient B6 animals received 11Gy on day -1 and were injected with of 5 million host type SAHA treated or control DCs on days −1, 0, and +2. Mice were transplanted on day 0 with 2 x 106 T cells and 5 x 106 BM from either syngeneic B6 or allogeneic BALB/c donors. Injection of SAHA treated DCs resulted in significantly better survival (60% vs. 10%, P < 0.01) and significantly reduced serum levels of TNF-α, donor T cell expansion and histopathology of GVHD on day +7 after BMT compared to the controls. We conclue that HDAC inhibitors are novel immunomodulators that regulate DC function and might represent a novel strategy to prevent GVHD.

scholarly journals Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1239-1249 ◽  
Author(s):  
Deborah W. Hendricks ◽  
Pamela J. Fink
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Interleukin 4 ◽  
T Helper ◽  
Recent Thymic Emigrants ◽  
Antibody Isotype ◽  
Helper Type

Abstract After intrathymic development, T cells exit the thymus and join the peripheral T-cell pool. Such recent thymic emigrants (RTEs) undergo both phenotypic and functional maturation during the first 3 weeks they reside in the periphery. Using a well-controlled in vitro polarization scheme, we now show that CD4+ RTEs are defective in T-helper (Th) type 0 (Th0), Th1, Th17, and regulatory T-cell lineage commitment, with dampened cytokine production and transcription factor expression. In contrast, CD4+ RTES are biased toward the Th2 lineage both in vitro and in vivo, with more robust interleukin-4, interleukin-5, and interleukin-13 production than their mature naive counterparts. Coculture experiments demonstrate that mature naive T cells influence neighboring RTEs in their Th responses. In adoptive hosts, CD4+ RTEs drive production of the Th2-associated antibody isotype immunoglobulin G1 and mediate airway inflammatory disease. This bias in RTEs likely results from dampened negative regulation of the Th2 lineage by diminished levels of T-bet, a key Th1 transcription factor. CD4+ RTEs thus represent a transitional population with a distinct interpretation of, and response to, immunologic cues. These characteristics may be beneficial during the postthymic maturation period by leading to the avoidance of inappropriate immune responses, particularly in lymphopenic neonates and adults.

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