The Immune Fulcrum

Richert-Spuhler, Laura E.; Lund, Jennifer M.

doi:10.1016/bs.pmbts.2015.07.015

Cited by 27 publications

(11 citation statements)

References 154 publications

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“…In the setting of infection, the role of Tregs is complex and appears to be specific to a given pathogen. While some studies have shown that Tregs are detrimental to successful immune responses and in some cases can lead to establishment of chronic infection, others have shown that Tregs limit immunopathology (10, 14–17). Studies of respiratory virus infections have yielded conflicting data about the role of Tregs in these different models.…”

Section: Introductionmentioning

confidence: 99%

CD4+ Regulatory T Cells Exert Differential Functions during Early and Late Stages of the Immune Response to Respiratory Viruses

Rogers

Lamens

Shafagati

et al. 2018

The Journal of Immunology

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Acute respiratory virus infection (ARI) induces CD8 T cells with diminished cytokine production and functional impairment. The role of cellular mediators of immune impairment, specifically CD4 regulatory T cells (Tregs), is incompletely understood in ARI. Tregs are known suppressors of effector T cell function, but whether they are detrimental or beneficial in ARI remains controversial. We show in this paper that Treg depletion leads to increased CD8 T cell function and lower virus titer in mice infected with human metapneumovirus. We further demonstrate that Tregs play a temporal role in the immune response to human metapneumovirus and influenza: Treg depletion before infection pathologically reduces virus-specific CD8 T cell numbers and delays virus clearance, whereas depletion 2 d postinoculation enhances CD8 T cell functionality without reducing virus-specific CD8 T cell numbers. Mechanistically, Treg depletion during immune priming led to impaired dendritic cell and CD8 T cell migration. Further, early Treg depletion was associated with immune skewing toward a type 2 phenotype characterized by increased type 2 innate lymphoid cells and T2 CD4 T cells, which was not observed when Treg depletion was delayed until after inoculation. These results indicate that the presence of Tregs at inoculation is critical for efficient priming of the CD8 T cell response to ARI, whereas later in infection, Tregs are dispensable for virus clearance.

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Section: Introductionmentioning

confidence: 99%

CD4+ Regulatory T Cells Exert Differential Functions during Early and Late Stages of the Immune Response to Respiratory Viruses

Rogers

Lamens

Shafagati

et al. 2018

The Journal of Immunology

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“…Our results presented herein further support that an increased basal frequency of Tregs in the circulation correlates with protection both from early SARS-CoV viral replication, as well as from disease upon infection ( Figures 2 and 4 ). In the context of multiple viral infections, we and others have found that Tregs are critical to orchestrate proper anti-viral immune responses ( Lanteri et al, 2009 ; Lund et al, 2008 ; Pattacini et al, 2016 ; Ruckwardt et al, 2009 ; Soerens et al, 2016 ), while it has also been found that Tregs in the context of infections, including respiratory infections such as RSV and influenza, can assist in protecting the host from excessive immunopathology ( Belkaid and Tarbell, 2009 ; Brincks et al, 2013 ; Lee et al, 2010 ; Loebbermann et al, 2012 ; Richert-Spuhler and Lund, 2015 ; Smigiel et al, 2014 ). Thus, our results here further support the concept that balance between anti-viral immunity and immunoregulation is essential to spare the host from both unrestricted viral replication as well as severe disease after infection.…”

Section: Discussionmentioning

confidence: 98%

Baseline T cell immune phenotypes predict virologic and disease control upon SARS-CoV infection

Graham

Swarts

Leist

et al. 2020

Preprint

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The COVID-19 pandemic has revealed that infection with SARS-CoV-2 can result in a wide range of clinical outcomes in humans, from asymptomatic or mild disease to severe disease that can require mechanical ventilation. An incomplete understanding of immune correlates of protection represents a major barrier to the design of vaccines and therapeutic approaches to prevent infection or limit disease. This deficit is largely due to the lack of prospectively collected, pre-infection samples from indiviuals that go on to become infected with SARS-CoV-2. Here, we utilized data from a screen of genetically diverse mice from the Collaborative Cross (CC) infected with SARS-CoV to determine whether circulating baseline T cell signatures are associated with a lack of viral control and severe disease upon infection. SARS-CoV infection of CC mice results in a variety of viral load trajectories and disease outcomes. Further, early control of virus in the lung correlates with an increased abundance of activated CD4 and CD8 T cells and regulatory T cells prior to infections across strains. A basal propensity of T cells to express IFNg and IL17 over TNFa also correlated with early viral control. Overall, a dysregulated, pro-inflammatory signature of circulating T cells at baseline was associated with severe disease upon infection. While future studies of human samples prior to infection with SARS-CoV-2 are required, our studies in mice with SARS-CoV serve as proof of concept that circulating T cell signatures at baseline can predict clinical and virologic outcomes upon SARS-CoV infection. Identification of basal immune predictors in humans could allow for identification of individuals at highest risk of severe clinical and virologic outcomes upon infection, who may thus most benefit from available clinical interventions to restrict infection and disease.SummaryWe used a screen of genetically diverse mice from the Collaborative Cross infected with mouse-adapted SARS-CoV in combination with comprehensive pre-infection immunophenotyping to identify baseline circulating immune correlates of severe virologic and clinical outcomes upon SARS-CoV infection.

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“…The role of Tregs has been controversial for a long time, as it was related to counterbalance Th1 response ( 79 ). This concept was progressively refined, placing Tregs in a more neutral role, without increasing the bacillary load in lesions at all ( 80 ), or even a protective one ( 81 , 82 ). The fact is that the models that were used did not develop human-like lesions, and therefore, the role of pathology and exudative progression was not explored.…”

Section: The Quest For a New Vaccine Against Tbmentioning

confidence: 99%

What We Have Learned and What We Have Missed in Tuberculosis Pathophysiology for a New Vaccine Design: Searching for the “Pink Swan”

Cardona

2017

Front. Immunol.

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This is a call to encourage the search for a new vaccine to stop the progression of Mycobacterium tuberculosis infection to tuberculosis (TB) disease. TB is a highly discreet and stigmatized disease, with a massive impact on human health. It has killed 1.2 billion people in the last 200 years and still kills 1.5 million people per year. Over the last 20 years, the TB vaccine field has experienced spectacular developments, and we have learned about (1) the importance of the Th1 response in controlling infection, mainly against RD1 and Ag85 antigens; (2) the stability of the antigenic repertoire; (3) the dynamics of M. tuberculosis granulomas; or (4) the link between typical and atypical pulmonary TB and the immune status of the host. However, we still do not (1) know how to avoid M. tuberculosis infection and reinfection; (2) understand the major role of the increase in lesion size in progression from infection to disease; (3) the role of interlobular septa in encapsulating pulmonary lesions; or (4) the role of neutrophilic infiltration and an exaggerated inflammatory response in the development of TB disease. These are strong reasons to pursue new, imaginative proposals involving both the antibody response and a balanced, tolerant immune response that averts progression toward TB. So far, the scientific mindset has been quite monolithic and has mainly focused on the stimulation of conventional T cells. But this approach has failed. For that reason, we are seeking unconventional perspectives to find a “pink swan,” a more efficacious and safer vaccine candidate.

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The Immune Fulcrum

Cited by 27 publications

References 154 publications

CD4+ Regulatory T Cells Exert Differential Functions during Early and Late Stages of the Immune Response to Respiratory Viruses

CD4+ Regulatory T Cells Exert Differential Functions during Early and Late Stages of the Immune Response to Respiratory Viruses

Baseline T cell immune phenotypes predict virologic and disease control upon SARS-CoV infection

What We Have Learned and What We Have Missed in Tuberculosis Pathophysiology for a New Vaccine Design: Searching for the “Pink Swan”

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