scholarly journals Alternatively activated dendritic cells regulate CD4+ T-cell polarization in vitro and in vivo

2012 ◽  
Vol 109 (25) ◽  
pp. 9977-9982 ◽  
Author(s):  
P. C. Cook ◽  
L. H. Jones ◽  
S. J. Jenkins ◽  
T. A. Wynn ◽  
J. E. Allen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cell Polarization ◽  
Cd4 T Cell ◽  
T Cell Polarization ◽  
Alternatively Activated

scholarly journals In silico design of Phl p 6 variants with altered folding stability significantly impacts antigen processing, immunogenicity and immune polarization

2020 ◽  
Author(s):  
Petra Winter ◽  
Stefan Stubenvoll ◽  
Sandra Scheiblhofer ◽  
Isabella A Joubert ◽  
Lisa Strasser ◽  
...  
Keyword(s):  
Thermal Stability ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Point Mutations ◽  
Cell Polarization ◽  
T Cell Polarization ◽  
Fold Stability

AbstactIntroductionProtein fold stability has been proposed to represent an intrinsic feature contributing to immunogenicity and immune polarization by influencing the amount of peptide-MHC II complexes (pMHCII). Using in silico prediction, we introduced point mutations in proteins that either increase or decrease their fold-stability without altering immunodominant epitopes or changing the overall structure of the protein. Here, we investigated how modulation of the fold-stability of the grass pollen allergen Phl p 6 affects its ability to stimulate immune responses and T cell polarization.MethodsUsing the MAESTRO software tool, stabilizing or destabilizing mutations were selected and verified by molecular dynamics simulations. The mutants were expressed in E. coli, purified tag-free, and analyzed for thermal stability and resistance to endolysosomal proteases. The resulting peptides were analysed by degradome assay and mass spectrometry. The structure of the most stable mutant protein was obtained by X-ray crystallography. We evaluated the capacity of the mutants to stimulate T cell proliferation in vitro, as well as antibody responses and T cell polarization in vivo in an adjuvant-free BALB/c mouse model.ResultsFour stabilizing and two destabilizing mutations were identified by MAESTRO. Experimentally determined changes in thermal stability compared to the wild type protein ranged from -5 to +14 °C. Destabilization led to faster proteolytic processing in vitro, whereas highly stabilized mutants were degraded very slowly. However, the overall pattern of identified peptides remained very similar. This was confirmed in bone marrow derived dendritic cells that processed and presented the immune dominant epitope from a destabilized mutant more efficiently. In vivo, stabilization resulted in a shift in immune polarization as indicated by higher levels of IgG2a and increased secretion of TH1/TH17 cytokines.ConclusionMAESTRO was very efficient in detecting single point mutations that increase or reduce fold-stability. Thermal stability correlated well with susceptibility to protease resistance and presentation of pMHCII on the surface of dendritic cells in vitro. This change in processing kinetics significantly influenced the polarization of T cell responses in vivo. Modulating the fold-stability of proteins thus has the potential to optimize and polarize immune responses, which opens the door to more efficient design of molecular vaccines.

scholarly journals T-Cell-Receptor-Dependent Signal Intensity Dominantly Controls CD4+ T Cell Polarization In Vivo

Immunity ◽  
2014 ◽  
Vol 41 (1) ◽  
pp. 63-74 ◽  
Author(s):  
Nicholas van Panhuys ◽  
Frederick Klauschen ◽  
Ronald N. Germain
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Signal Intensity ◽  
Cell Receptor ◽  
Cell Polarization ◽  
Cd4 T Cell ◽  
Dependent Signal ◽  
T Cell Polarization

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 Impairment of CD4+ T Cell Polarization by Dengue Virus–Infected Dendritic Cells

2011 ◽  
Vol 203 (12) ◽  
pp. 1763-1774 ◽  
Author(s):  
Amanda J. Chase ◽  
Freddy A. Medina ◽  
Jorge L. Muñoz-Jordán
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Dengue Virus ◽  
Cell Polarization ◽  
Cd4 T Cell ◽  
T Cell Polarization

Regulatory dendritic cells program generation of interleukin-4–producing alternative memory CD4 T cells with suppressive activity

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1218-1227 ◽  
Author(s):  
Xiongfei Xu ◽  
Zhenhong Guo ◽  
Xueyu Jiang ◽  
Yushi Yao ◽  
Qiangguo Gao ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Interleukin 4 ◽  
Delayed Type Hypersensitivity ◽  
Regulatory Function

Abstract The heterogeneity and mechanisms for the generation of CD4 memory T (CD4 Tm) cells remain elusive. Distinct subsets of dendritic cells (DCs) have been found to regulate a distinct T-helper (Th)–cell subset differentiation by influencing cytokine cues around CD4 T cells; however, whether and how the regulatory DC subset can regulate Tm-cell differentiation remains unknown. Further, there is no ideal in vitro experimental system with which to mimic the 3 phases of the CD4 T-cell immune response (expansion, contraction, memory generation) and/or to culture CD4 Tm cells for more than a month. By analyzing CD4 T cells programmed by long-term coculture with regulatory DCs, we identified a population of long-lived CD4 T cells with a CD44hiCD62L−CCR7− effector memory phenotype and rapid, preferential secretion of the Th2 cytokines interleukin-4 (IL-4), IL-5, IL-10, and IL-13 after antigenic stimulation. These regulatory DC-programmed Tm cells suppress CD4 T-cell activation and proliferation in vitro via IL-10 and inhibit the delayed-type hypersensitivity response once infused in vivo. We also identify their natural counterpart, which is up-regulated by regulatory DC transfusion and negatively regulates the recall response in vivo. Different from interferon-γ–producing conventional Tm cells, these IL-4–producing CD4 Tm cells act as alternative Tm cells with a regulatory function, suggesting a new way of negative immune regulation by memory T cells.

scholarly journals Relative Contributions of B Cells and Dendritic Cells from Lupus-Prone Mice to CD4+ T Cell Polarization

2018 ◽  
Vol 200 (9) ◽  
pp. 3087-3099 ◽  
Author(s):  
Seung-Chul Choi ◽  
Zhiwei Xu ◽  
Wei Li ◽  
Hong Yang ◽  
Derry C. Roopenian ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Polarization ◽  
Cd4 T Cell ◽  
T Cell Polarization

Presentation of proteins encapsulated in sterically stabilized liposomes by dendritic cells initiates CD8+ T-cell responses in vivo

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3505-3513 ◽  
Author(s):  
Ralf Ignatius ◽  
Karsten Mahnke ◽  
Miguel Rivera ◽  
Keelung Hong ◽  
Frank Isdell ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Soluble Protein ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Sterically Stabilized Liposomes

Liposomes have been proposed as a vehicle to deliver proteins to antigen-presenting cells (APC), such as dendritic cells (DC), to stimulate strong T cell–mediated immune responses. Unfortunately, because of their instability in vivo and their rapid uptake by cells of the mononuclear phagocyte system on intravenous administration, most types of conventional liposomes lack clinical applicability. In contrast, sterically stabilized liposomes (SL) have increased in vivo stability. It is shown that both immature and mature DC take up SL into neutral or mildly acidic compartments distinct from endocytic vacuoles. These DC presented SL-encapsulated protein to both CD4+ and CD8+ T cells in vitro. Although CD4+ T-cell responses were comparable to those induced by soluble protein, CD8+ T-cell proliferation was up to 300-fold stronger when DC had been pulsed with SL-encapsulated ovalbumin. DC processed SL-encapsulated antigen through a TAP-dependent mechanism. Immunization of mice with SL-encapsulated ovalbumin led to antigen presentation by DC in vivo and stimulated greater CD8+ T-cell responses than immunization with soluble protein or with conventional or positively charged liposomes carrying ovalbumin. Therefore, the application of SL-encapsulated antigens offers a novel effective, safe vaccine approach if a combination of CD8+and CD4+ T-cell responses is desired (ie, in anti-viral or anti-tumor immunity).

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