35 research outputs found
Primed T Cell Responses to Chemokines Are Regulated by the Immunoglobulin-Like Molecule CD31
CD31, an immunoglobulin-like molecule expressed by leukocytes and endothelial cells, is thought to contribute to the physiological regulation T cell homeostasis due to the presence of two immunotyrosine-based inhibitory motifs in its cytoplasmic tail. Indeed, loss of CD31 expression leads to uncontrolled T cell-mediated inflammation in a variety of experimental models of disease and certain CD31 polymorphisms correlate with increased disease severity in human graft-versus-host disease and atherosclerosis. The molecular mechanisms underlying CD31-mediated regulation of T cell responses have not yet been clarified. We here show that CD31-mediated signals attenuate T cell chemokinesis both in vitro and in vivo. This effect selectively affects activated/memory T lymphocytes, in which CD31 is clustered on the cell membrane where it segregates to the leading edge. We provide evidence that this molecular segregation, which does not occur in naĂŻve T lymphocytes, might lead to cis-CD31 engagement on the same membrane and subsequent interference with the chemokine-induced PI3K/Akt signalling pathway. We propose that CD31-mediated modulation of memory T cell chemokinesis is a key mechanism by which this molecule contributes to the homeostatic regulation of effector T cell immunity
Self-recognition of the endothelium enables regulatory T-cell trafficking and defines the kinetics of immune regulation
This study was supported by the British Heart Foundation (PG 09/002/
2642). AJR is funded by Kingâs College London British Heart Foundation Centre of
Excellence and EI was supported by the Department of Health via National Institute
for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guyâs
and St Tomasâ NHF Foundation Trust in partnership with Kingâs College London and
Kingâs College Hospital NHS Foundation Trust. BG was supported by a British Heart
Foundation studentship (FS/10/009/28166) and DC by an Arthritis Research UK
Fellowship (18103)
Genetic or pharmaceutical blockade of phosphoinositide 3-kinase p110ÎŽ prevents chronic rejection of heart allografts.
Chronic rejection is the major cause of long-term heart allograft failure, characterized by tissue infiltration by recipient T cells with indirect allospecificity. Phosphoinositol-3-kinase p110ÎŽ is a key mediator of T cell receptor signaling, regulating both T cell activation and migration of primed T cells to non-lymphoid antigen-rich tissue. We investigated the effect of genetic or pharmacologic inactivation of PI3K p110ÎŽ on the development of chronic allograft rejection in a murine model in which HY-mismatched male hearts were transplanted into female recipients. We show that suppression of p110ÎŽ activity significantly attenuates the development of chronic rejection of heart grafts in the absence of any additional immunosuppressive treatment by impairing the localization of antigen-specific T cells to the grafts, while not inducing specific T cell tolerance. p110ÎŽ pharmacologic inactivation is effective when initiated after transplantation. Targeting p110ÎŽ activity might be a viable strategy for the treatment of heart chronic rejection in humans
Mechanisms of T cell organotropism
F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation
International Consensus Statement on Rhinology and Allergy: Rhinosinusitis
Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICARâRS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICARâRSâ2021 as well as updates to the original 140 topics. This executive summary consolidates the evidenceâbased findings of the document. Methods: ICARâRS presents over 180 topics in the forms of evidenceâbased reviews with recommendations (EBRRs), evidenceâbased reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICARâRSâ2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidenceâbased management algorithm is provided. Conclusion: This ICARâRSâ2021 executive summary provides a compilation of the evidenceâbased recommendations for medical and surgical treatment of the most common forms of RS
A novel CXCL10-based GPI-anchored fusion protein as adjuvant in NK-based tumor therapy
BACKGROUND: Cellular therapy is a promising therapeutic strategy for malignant diseases. The efficacy of this therapy can be limited by poor infiltration of the tumor by immune effector cells. In particular, NK cell infiltration is often reduced relative to T cells. A novel class of fusion proteins was designed to enhance the recruitment of specific leukocyte subsets based on their expression of a given chemokine receptor. The proteins are composed of an N-terminal chemokine head, the mucin domain taken from the membrane-anchored chemokine CX3CL1, and a C-terminal glycosylphosphatidylinositol (GPI) membrane anchor replacing the normal transmembrane domain allowing integration of the proteins into cell membranes when injected into a solid tumor. The mucin domain in conjunction with the chemokine head acts to specifically recruit leukocytes expressing the corresponding chemokine receptor. METHODOLOGY/PRINCIPAL FINDINGS: A fusion protein comprising a CXCL10 chemokine head (CXCL10-mucin-GPI) was used for proof of concept for this approach and expressed constitutively in Chinese Hamster Ovary cells. FPLC was used to purify proteins. The recombinant proteins efficiently integrated into cell membranes in a process dependent upon the GPI anchor and were able to activate the CXCR3 receptor on lymphocytes. Endothelial cells incubated with CXCL10-mucin-GPI efficiently recruited NK cells in vitro under conditions of physiologic flow, which was shown to be dependent on the presence of the mucin domain. Experiments conducted in vivo using established tumors in mice suggested a positive effect of CXCL10-mucin-GPI on the recruitment of NK cells. CONCLUSIONS: The results suggest enhanced recruitment of NK cells by CXCL10-mucin-GPI. This class of fusion proteins represents a novel adjuvant in cellular immunotherapy. The underlying concept of a chemokine head fused to the mucin domain and a GPI anchor signal sequence may be expanded into a broader family of reagents that will allow targeted recruitment of cells in various settings
ImunopatogĂȘnese da psorĂase: revisando conceitos Reviewing concepts in the immunopathogenesis of psoriasis
O conhecimento sobre a fisiopatogenia da psorĂase possibilitou o desenvolvimento de ferramentas terapĂȘuticas que visam ao bloqueio do seu gatilho imunolĂłgico. Paralelamente, citocinas como o TNF tĂȘm sido reconhecidas como integrantes da etiopatogenia da psorĂase e comorbidades a ela relacionadas. Estudos genĂ©ticos e epidemiolĂłgicos contribuĂram efetivamente para as conclusĂ”es a que se tem chegado atualmente sobre esta complexa patologia.<br>Insights into the pathogenesis of psoriasis led to the development of therapeutic tools aimed at blocking its immunological trigger. In parallel, cytokines such as the tumor necrosis factor (TNF) have been recognized as playing a crucial role in the pathogenesis of psoriasis and its associated comorbidities. Genetic and immunological studies have contributed effectively towards establishing the currently held concepts regarding this complex disease