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.

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 Gene Doping with Peroxisome-Proliferator-Activated Receptor Beta/Delta Agonists Alters Immunity but Exercise Training Mitigates the Detection of Effects in Blood Samples

2021 ◽  
Vol 22 (21) ◽  
pp. 11497
Author(s):  
Brigitte Sibille ◽  
Isabelle Mothe-Satney ◽  
Gwenaëlle Le Menn ◽  
Doriane Lepouse ◽  
Sébastien Le Garf ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Exercise Training ◽  
Lymphoid Organs ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Blood Samples ◽  
Secondary Lymphoid Organs ◽  
Vitro Effect ◽  
Receptor Beta

Synthetic ligands of peroxisome-proliferator-activated receptor beta/delta (PPARβ/δ) are being used as performance-enhancing drugs by athletes. Since we previously showed that PPARβ/δ activation affects T cell biology, we wanted to investigate whether a specific blood T cell signature could be employed as a method to detect the use of PPARβ/δ agonists. We analyzed in primary human T cells the in vitro effect of PPARβ/δ activation on fatty acid oxidation (FAO) and on their differentiation into regulatory T cells (Tregs). Furthermore, we conducted studies in mice assigned to groups according to an 8-week exercise training program and/or a 6-week treatment with 3 mg/kg/day of GW0742, a PPARβ/δ agonist, in order to (1) determine the immune impact of the treatment on secondary lymphoid organs and to (2) validate a blood signature. Our results show that PPARβ/δ activation increases FAO potential in human and mouse T cells and mouse secondary lymphoid organs. This was accompanied by increased Treg polarization of human primary T cells. Moreover, Treg prevalence in mouse lymph nodes was increased when PPARβ/δ activation was combined with exercise training. Lastly, PPARβ/δ activation increased FAO potential in mouse blood T cells. Unfortunately, this signature was masked by training in mice. In conclusion, beyond the fact that it is unlikely that this signature could be used as a doping-control strategy, our results suggest that the use of PPARβ/δ agonists could have potential detrimental immune effects that may not be detectable in blood samples.

scholarly journals The Par polarity complex regulates Rap1- and chemokine-induced T cell polarization

2007 ◽  
Vol 176 (6) ◽  
pp. 863-875 ◽  
Author(s):  
Audrey Gérard ◽  
Alexander E.E. Mertens ◽  
Rob A. van der Kammen ◽  
John G. Collard
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Polarity ◽  
Intracellular Localization ◽  
Transendothelial Migration ◽  
Induced Polarization ◽  
Cell Polarization ◽  
Molecular Pathways ◽  
T Cell Polarization ◽  
Actin Remodelling

Cell polarization is required for virtually all functions of T cells, including transendothelial migration in response to chemokines. However, the molecular pathways that establish T cell polarity are poorly understood. We show that the activation of the partitioning defective (Par) polarity complex is a key event during Rap1- and chemokine-induced T cell polarization. Intracellular localization and activation of the Par complex are initiated by Rap1 and require Cdc42 activity. The Rac activator Tiam1 associates with both Rap1 and components of the Par complex, and thereby may function to connect the Par polarity complex to Rap1 and to regulate the Rac-mediated actin remodelling required for T cell polarization. Consistent with these findings, Tiam1-deficient T cells are impaired in Rap1- and chemokine-induced polarization and chemotaxis. Our studies implicate Tiam1 and the Par polarity complex in polarization of T cells, and provide a mechanism by which chemokines and Rap1 regulate T cell polarization and chemotaxis.

scholarly journals In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 1113-1122 ◽  
Author(s):  
Andreas Beilhack ◽  
Stephan Schulz ◽  
Jeanette Baker ◽  
Georg F. Beilhack ◽  
Courtney B. Wieland ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Lymphoid Organs ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Host Disease ◽  
Graft Versus Host ◽  
Secondary Lymphoid Organs

AbstractGraft-versus-host disease (GVHD) is a major obstacle in allogeneic hematopoietic cell transplantation. Given the dynamic changes in immune cell subsets and tissue organization, which occur in GVHD, localization and timing of critical immunological events in vivo may reveal basic pathogenic mechanisms. To this end, we transplanted luciferase-labeled allogeneic splenocytes and monitored tissue distribution by in vivo bioluminescence imaging. High-resolution analyses showed initial proliferation of donor CD4+ T cells followed by CD8+ T cells in secondary lymphoid organs with subsequent homing to the intestines, liver, and skin. Transplantation of purified naive T cells caused GVHD that was initiated in secondary lymphoid organs followed by target organ manifestation in gut, liver, and skin. In contrast, transplanted CD4+ effector memory T (TEM) cells did not proliferate in secondary lymphoid organs in vivo and despite their in vitro alloreactivity in mixed leukocyte reaction (MLR) assays did not cause acute GVHD. These findings underline the potential of T-cell subsets with defined trafficking patterns for immune reconstitution without the risk of GVHD.

scholarly journals Mice Lacking Expression of the Chemokines Ccl21-Ser and Ccl19 (plt Mice) Demonstrate Delayed but Enhanced T Cell Immune Responses

2001 ◽  
Vol 193 (2) ◽  
pp. 207-218 ◽  
Author(s):  
Shigeyuki Mori ◽  
Hideki Nakano ◽  
Kentaro Aritomi ◽  
Chrong-Reen Wang ◽  
Michael D. Gunn ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cell Response ◽  
T Cell Response ◽  
Lymphoid Organs ◽  
Cell Responses ◽  
T Cell Immune Responses ◽  
Secondary Lymphoid Organs

The paucity of lymph node T cells (plt) mutation leads to a loss of CCL21 and CCL19 expression in secondary lymphoid organs. plt mice have defects in the migration of naive T cells and activated dendritic cells into the T cell zones of lymphoid organs, suggesting that they would have defects in T cell immune responses. We now demonstrate T cell responses in plt mice are delayed but ultimately enhanced. Responses to contact sensitization are decreased at day 2 after priming but increased at day 6. After subcutaneous immunization, antigen-specific T cell proliferation and cytokine production in plt mice are increased and remain markedly elevated for at least 8 wk. Compared with wild-type mice, a proportion of T cell response in plt mice are shifted to the spleen, and prior splenectomy reduces the T cell response in draining lymph nodes. After immunization of plt mice, T cells and dendritic cells colocalize in the superficial cortex of lymph nodes and in splenic bridging channels, but not in T cell zones. These results demonstrate that plt mice mount robust T cell responses despite the failure of naive T cells and activated dendritic cells to enter the thymus dependent areas of secondary lymphoid organs.

scholarly journals Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2919-2928 ◽  
Author(s):  
Andreas Beilhack ◽  
Stephan Schulz ◽  
Jeanette Baker ◽  
Georg F. Beilhack ◽  
Ryosei Nishimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Effector T Cells ◽  
Lymphoid Organs ◽  
Cell Entry ◽  
Host Disease ◽  
Graft Versus Host ◽  
Secondary Lymphoid Organs ◽  
Acute Graft

In acute graft-versus-host disease (aGVHD), donor T cells attack the recipient's gastrointestinal tract, liver, and skin. We hypothesized that blocking access to distinct lymphoid priming sites may alter the specific organ tropism and prevent aGVHD development. In support of this initial hypothesis, we found that different secondary lymphoid organs (SLOs) imprint distinct homing receptor phenotypes on evolving alloreactive effector T cells in vivo. Yet preventing T-cell entry to specific SLOs through blocking monoclonal antibodies, or SLO ablation, did not alter aGVHD pathophysiology. Moreover, transfer of alloreactive effector T cells into conditioned secondary recipients targeted the intestines and liver, irrespective of their initial priming site. Thus, we demonstrate redundancy of SLOs at different anatomical sites in aGVHD initiation. Only prevention of T-cell entry to all SLOs could completely abrogate the onset of aGVHD.

scholarly journals Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Peter Jan Hooikaas ◽  
Hugo GJ Damstra ◽  
Oane J Gros ◽  
Wilhelmina E van Riel ◽  
Maud Martin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immunological Synapse ◽  
Cell Polarization ◽  
Contact Site ◽  
Cell Form ◽  
Pulling Forces ◽  
T Cell Polarization ◽  
Microtubule Growth ◽  
Antigen Presenting

When a T cell and an antigen-presenting cell form an immunological synapse, rapid dynein-driven translocation of the centrosome towards the contact site leads to reorganization of microtubules and associated organelles. Currently, little is known about how the regulation of microtubule dynamics contributes to this process. Here, we show that the knockout of KIF21B, a kinesin-4 linked to autoimmune disorders, causes microtubule overgrowth and perturbs centrosome translocation. KIF21B restricts microtubule length by inducing microtubule pausing typically followed by catastrophe. Catastrophe induction with vinblastine prevented microtubule overgrowth and was sufficient to rescue centrosome polarization in KIF21B-knockout cells. Biophysical simulations showed that a relatively small number of KIF21B molecules can restrict microtubule length and promote an imbalance of dynein-mediated pulling forces that allows the centrosome to translocate past the nucleus. We conclude that proper control of microtubule length is important for allowing rapid remodeling of the cytoskeleton and efficient T cell polarization.

scholarly journals Human Dendritic Cells Skew Isotype Switching of CD40-activated Naive B Cells towards IgA1 and IgA2

1997 ◽  
Vol 185 (11) ◽  
pp. 1909-1918 ◽  
Author(s):  
Jérôme Fayette ◽  
Bertrand Dubois ◽  
Stéphane Vandenabeele ◽  
Jean-Michel Bridon ◽  
Béatrice Vanbervliet ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Culture Conditions ◽  
Lymphoid Organs ◽  
Cell Growth And Differentiation ◽  
Secondary Lymphoid Organs

Within T cell–rich areas of secondary lymphoid organs, interdigitating dendritic cells recruit antigen-specific T cells that then induce B cells to secrete Igs. This study investigates the possible role(s) of dendritic cells in the regulation of human B cell responses. In the absence of exogenous cytokines, in vitro generated dendritic cells (referred to as Dendritic Langerhans cells, D-Lc) induced surface IgA expression on ∼10% of CD40-activated naive sIgD+ B cells. In the presence of IL-10 and TGF-β, a combination of cytokines previously identified for its capacity to induce IgA switch, D-Lc strongly potentiated the induction of sIgA on CD40-activated naive B cells from 5% to 40–50%. D-Lc alone did not induce the secretion of IgA by CD40-activated naive B cells, which required further addition of IL-10. Furthermore, D-Lc skewed towards the IgA isotype at the expense of IgG, the Ig production of CD40-activated naive B cells cultured in the presence of IL-10 and TGF-β. Importantly, under these culture conditions, both IgA1 and IgA2 were detected. In the presence of IL-10, secretion of IgA2 by CD40-activated naive B cells could be detected only in response to D-Lc and was further enhanced by TGF-β. Collectively, these results suggest that in addition to activating T cells in the extrafollicular areas of secondary lymphoid organs, human D-Lc also directly modulate T cell–dependent B cell growth and differentiation, by inducing the IgA isotype switch.

Prevention of Acute Graft-Versus-Host Disease by CD4+CD25+ Regulatory T Cells Is Dependent on the CD30/CD153 Pathway.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1299-1299 ◽  
Author(s):  
Robert Zeiser ◽  
Vu Nguyen ◽  
Martin Buess ◽  
Mobin Karimi ◽  
Pia Bjorck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Graft Versus Host Disease ◽  
Lymphoid Organs ◽  
Mouse Strains ◽  
Host Disease ◽  
Graft Versus Host ◽  
Secondary Lymphoid Organs ◽  
Acute Graft

Abstract CD4+CD25+ regulatory T (Treg) cells suppress acute graft versus host disease (aGVHD), prevent autoimmunity and delay allograft rejection. CD30 and other TNF-R family members have been demonstrated to be expressed by Treg and to function as alternative costimulatory pathways for T cell activation. In this study we assessed the significance of the CD30/CD153 pathway in Tregs suppression of aGVHD in a murine major MHC mismatch BMT model. Using bioluminescence imaging proliferation of donor derived luciferase-labeled CD4+ and CD8+ T cells was quantified at serial time points after transplantation. Treg suppressed the early expansion of alloreactive T-cells. Immunofluorescence microscopy revealed a predominant infiltration of donor derived Treg in CD153 positive regions of secondary lymphoid organs, namely parafollicular T cell zones of lymph nodes and the subepithelial dome regions of Peyers Patches. In vivo blockade of the CD30/CD153 pathway with anti CD153 Ab did not alter Treg migration to secondary lymphoid organs but reduced their suppressive effect. Proliferation of donor T cells as measured in photons/second/mouse was significantly higher in animals receiving Treg and CD153 blocking antibodies as compared to recipients of Treg only (p=0.0038). Gene expression profiling of Treg with DNA microarrays indicated a Treg signature that was consistently found in different mouse strains. This Treg signature was altered after CD153 blockade in vitro. Importantly, aGVHD lethality was significantly increased (p=0.021) when CD30-CD153 interaction was blocked during Treg transfer. This study provides direct evidence that the TNF-R family member CD30 is critical for Treg cell function in the regulation of pathological T cell responses that lead to aGVHD.

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