37 research outputs found
Human Immunodeficiency Virus Playing Hide-and-Seek: Understanding the TFH Cell Reservoir and Proposing Strategies to Overcome the Follicle Sanctuary
Human immunodeficiency virus (HIV) infects millions of people worldwide, and new cases continue to emerge. Once infected, the virus cannot be cleared by the immune system and causes acquired immunodeficiency syndrome. Combination antiretroviral therapeutic regimen effectively suppresses viral replication and halts disease progression. The treatment, however, does not eliminate the virus-infected cells, and interruption of treatment inevitably leads to viral rebound. The rebound virus originates from a group of virus-infected cells referred to as the cellular reservoir of HIV. Identifying and eliminating the HIV reservoir will prevent viral rebound and cure HIV infection. In this review, we focus on a recently discovered HIV reservoir in a subset of CD4+ TÂ cells called the follicular helper T (TFH) cells. We describe the potential mechanisms for the emergence of reservoir in TFH cells, and the strategies to target and eliminate this viral reservoir.This work is supported by the National Health and Medical
Research Council of Australia (YL; GNT1085509 to DY), the
amfAR Research Consortium on HIV Eradication (109327-
59-RGRL, DY), The Creative and Novel Ideas in HIV Research
Program of The International AIDS Society (DY), and Australian
Centre for HIV and Hepatitis Virology Research (2015-69 to DY
Human Immunodeficiency Virus Playing Hide-and-Seek: Understanding the TFH Cell Reservoir and Proposing Strategies to Overcome the Follicle Sanctuary
Human immunodeficiency virus (HIV) infects millions of people worldwide, and new cases continue to emerge. Once infected, the virus cannot be cleared by the immune system and causes acquired immunodeficiency syndrome. Combination antiretroviral therapeutic regimen effectively suppresses viral replication and halts disease progression. The treatment, however, does not eliminate the virus-infected cells, and interruption of treatment inevitably leads to viral rebound. The rebound virus originates from a group of virus-infected cells referred to as the cellular reservoir of HIV. Identifying and eliminating the HIV reservoir will prevent viral rebound and cure HIV infection. In this review, we focus on a recently discovered HIV reservoir in a subset of CD4+ T cells called the follicular helper T (TFH) cells. We describe the potential mechanisms for the emergence of reservoir in TFH cells, and the strategies to target and eliminate this viral reservoir
Impact of cardiac arrest centers on the survival of patients with nontraumatic outâofâhospital cardiac arrest : a systematic review and metaâanalysis
Background
The role of cardiac arrest centers (CACs) in outâofâhospital cardiac arrest care systems is continuously evolving. Interpretation of existing literature is limited by heterogeneity in CAC characteristics and types of patients transported to CACs. This study assesses the impact of CACs on survival in outâofâhospital cardiac arrest according to varying definitions of CAC and prespecified subgroups.
Methods and Results
Electronic databases were searched from inception to March 9, 2021 for relevant studies. Centers were considered CACs if selfâdeclared by study authors and capable of relevant interventions. Main outcomes were survival and neurologically favorable survival at hospital discharge or 30 days. Metaâanalyses were performed for adjusted odds ratio (aOR) and crude odds ratios. Thirtyâsix studies were analyzed. Survival with favorable neurological outcome significantly improved with treatment at CACs (aOR, 1.85 [95% CI, 1.52â2.26]), even when including highâvolume centers (aOR, 1.50 [95% CI, 1.18â1.91]) or including improvedâcare centers (aOR, 2.13 [95% CI, 1.75â2.59]) as CACs. Survival significantly increased with treatment at CACs (aOR, 1.92 [95% CI, 1.59â2.32]), even when including highâvolume centers (aOR, 1.74 [95% CI, 1.38â2.18]) or when including improvedâcare centers (aOR, 1.97 [95% CI, 1.71â2.26]) as CACs. The treatment effect was more pronounced among patients with shockable rhythm ( P =0.006) and without prehospital return of spontaneous circulation ( P =0.005). Conclusions were robust to sensitivity analyses, with no publication bias detected.
Conclusions
Care at CACs was associated with improved survival and neurological outcomes for patients with nontraumatic outâofâhospital cardiac arrest regardless of varying CAC definitions. Patients with shockable rhythms and those without prehospital return of spontaneous circulation benefited more from CACs. Evidence for bypassing hospitals or interhospital transfer remains inconclusive
CXCR5<sup>+</sup> follicular cytotoxic T cells control viral infection in B cell follicles
During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cellâderived malignancies
Understanding and Enhancing Cytotoxic T Lymphocytes Function for Anti-Viral Immunity
Chronic infections,
such as those caused by chronic human immunodeficiency virus (HIV) hepatitis B
virus (HBV), and Epstein-Barr virus (EBV), are global epidemics that lead to
life-long diseases and impose significant health burdens. Cytotoxic T
lymphocytes (CTLs) are a population of adaptive immune cells specialized in
cytolysis of infected cells. However, CTLs fail to eliminate chronic infections
in majority of cases. There are several mechanisms by which these viruses evade
eradication by CTLs. One of the mechanisms commonly used by both HIV and EBV is
to 'hide' inside B cell follicles in secondary lymphoid organs which contain
fewer CTLs. Another strategy is to induce the exhaustion of T cells, a
phenomenon which significantly reduces the CTLâs capability to eliminate viral
infections. This thesis aims to tackle the chronic infections from these two
angles. The thesis consists of two parts. In the first part, I describe a novel
population of CTLs that are able to migrate into B cell follicles and control
infections therein. In the second part, I characterised a novel monoclonal
antibody that potentiates the bioactivity of an immunostimulatory cytokine,
interleukin-21 (IL-21), which boosted the number and cytotoxicity of CTLs.
Enhancing the follicular entry and cytotoxic activity of CTLs provide feasible
therapeutic approaches to reduce viral infections, which may eventually lead to
the elimination of chronic infections such as HIV, HBV and EBV
Human immunodeficiency virus playing hide-and-Seek:Understanding the T<sub>FH</sub> cell reservoir and proposing strategies to overcome the follicle sanctuary
Human immunodeficiency virus (HIV) infects millions of people worldwide, and new cases continue to emerge. Once infected, the virus cannot be cleared by the immune system and causes acquired immunodeficiency syndrome. Combination antiretroviral therapeutic regimen effectively suppresses viral replication and halts disease progression. The treatment, however, does not eliminate the virus-infected cells, and interruption of treatment inevitably leads to viral rebound. The rebound virus originates from a group of virus-infected cells referred to as the cellular reservoir of HIV. Identifying and eliminating the HIV reservoir will prevent viral rebound and cure HIV infection. In this review, we focus on a recently discovered HIV reservoir in a subset of CD4(+) T cells called the follicular helper T (T-FH) cells. We describe the potential mechanisms for the emergence of reservoir in TFH cells, and the strategies to target and eliminate this viral reservoir
Efficient production of recombinant IL-21 proteins for pre-clinical studies by a two-step dilution refolding method
Produced by CD4(+) helper T cells and natural killer T (NKT) cells, interleukin-21 (IL-21) performs broad regulatory functions on B cells, CD4(+) T cells, CD8(+) T cells, NK cells and NKF cells. Targeting IL-21 to enhance the immune system has attracted great interests in the development of vaccination, anti-infection and anti-tumor therapies. Administration of IL-21 in pre-clinical models is however limited by relatively high expense of the recombinant IL-21 protein. Here, we report a rapid and cost-effective method to produce IL-21 using Escherichia coli (E. coli) by introducing a novel two-step dilution strategy for refolding. The method has been validated to produce milligrams of human IL-21, human IL-21/IL-4 chimera and mouse IL-21 with high bioactivities and low endotoxin, mostly suitable for in vitro and in vivo pre-clinical studies. (C) 2013 Elsevier B.V. All rights reserved
PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes the development of autoimmunity
Non-coding single nucleotide polymorphisms that repress PTPN2 expression have been linked with the development of type 1 diabetes, rheumatoid arthritis and Crohn's disease. PTPN2 attenuates CD8ĂŸ T cell responses to self and prevents overt autoreactivity in the context of T cell homeostasis and antigen crosspresentation. The role of PTPN2 in other immune subsets in the development of autoimmunity remains unclear. Here we show that the inducible deletion of PTPN2 in hematopoietic compartment of adult nonautoimmune prone mice results in systemic inflammation and autoimmunity. PTPN2-deficient mice had increased inflammatory monocytes, B cells and effector T cells in lymphoid and non-lymphoid tissues and exhibited symptoms of dermatitis, glomerulonephritis, pancreatitis and overt liver disease. Autoimmunity was characterised by the formation of germinal centers in the spleen and associated with
markedly increased germinal center B cells and T follicular helper (Tfh) cells and circulating anti-nuclear antibodies, inflammatory cytokines and immunoglobulins. CD8ĂŸ T cell proliferative responses were enhanced, and interleukin-21-induced STAT-3 signalling in Tfh cells and B cells was increased and accompanied by enhanced B cell proliferation ex vivo. These results indicate that deficiencies in PTPN2
across multiple immune lineages, including naive T cells, Tfh cells and B cells, contribute to the development of autoimmunityThis work
was supported by the National Health and Medical Research
Council (NHMRC) of Australia (1047055); T.T. is a NHMRC Principal
Research Fellow (1103037)
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Cellular Subcompartments through Cytoplasmic Streaming.
Cytoplasmic streaming occurs in diverse cell types, where it generally serves a transport function. Here, we examine streaming in multicellular fungal hyphae and identify an additional function wherein regimented streaming forms distinct cytoplasmic subcompartments. In the hypha, cytoplasm flows directionally from cell to cell through septal pores. Using live-cell imaging and computer simulations, we identify a flow pattern that produces vortices (eddies) on the upstream side of the septum. Nuclei can be immobilized in these microfluidic eddies, where they form multinucleate aggregates and accumulate foci of the HDA-2 histone deacetylase-associated factor, SPA-19. Pores experiencing flow degenerate in the absence of SPA-19, suggesting that eddy-trapped nuclei function to reinforce the septum. Together, our data show that eddies comprise a subcellular niche favoring nuclear differentiation and that subcompartments can be self-organized as a consequence of regimented cytoplasmic streaming