The Effector T Cell Response to Influenza Infection

Hufford, Matthew M.; Kim, Taeg S.; Sun, Jie; Braciale, Thomas J.

doi:10.1007/82_2014_397

Cited by 77 publications

(93 citation statements)

References 154 publications

(211 reference statements)

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“…In contrast, NP vaccinated cohorts of aged mice did not show any significant enhancement of CD4 T cell numbers in either spleen or lungs when compared to controls. Importantly, it is essential for these vaccine generated CD4 T cells to be recruited to the lungs during influenza infection in order to quickly and completely clear virus and resolve inflammation [31] and the lack of NP-specific T cells in the aged lungs could be a major contributor to slower resolution of infection.…”

Section: Resultsmentioning

confidence: 99%

Vaccine efficacy and T helper cell differentiation change with aging

et al. 2016

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Influenza and pneumonia are leading causes of death in elderly populations. With age, there is an increased inflammatory response and slower viral clearance during influenza infection which increases the risk of extended illness and mortality. Here we employ a preclinical murine model of influenza infection to examine the protective capacity of vaccination with influenza nucleoprotein (NP). While NP vaccination reduces influenza-induced lung inflammation in young mice, aged mice do not show this reduction, but are protected from influenza-induced mortality. Aged mice do make a significant amount of NP-specific IgG and adoptive transfer experiments show that NP antibody can protect from death but cannot reduce lung inflammation. Furthermore, young but not aged vaccinated mice generate significant numbers of NP-specific T cells following subsequent infection and few of these T cells are found in aged lungs early during infection. Importantly, aged CD4 T cells have a propensity to differentiate towards a T follicular helper (Tfh) phenotype rather than a T helper 1 (Th1) phenotype that predominates in the young. Since Th1 cells are important in viral clearance, reduced Th1 differentiation in the aged is critical and could account for some or all of the age-related differences in vaccine responses and infection resolution.

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Section: Resultsmentioning

confidence: 99%

Vaccine efficacy and T helper cell differentiation change with aging

et al. 2016

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“…In our studies, we observed that the virus-infected P2X7r KO mice had lower levels of proinflammatory cytokines such as IL-6, TNF-α, IFN-γ, CXCL10, and CCL2 in their lungs at day 3 postinfection. Activation of P2X7 receptors by extracellular ATP plays a central role in the release of proinflammatory cytokines, and it plays a role on the regulation of macrophages, neutrophils, and effector T cells, important cell mediators during inflammation (9, 11, 53, 54). Therefore, the lower level of cytokines observed in the lungs of the P2X7r KO mice after influenza virus infection may be explained by the lack of activation of this purinergic signaling pathway in these mice.…”

Section: Discussionmentioning

confidence: 99%

“…This discrepancy may be explained by the time when we measured IL-10 in the lungs, since the main contributors to IL-10 production in the context of influenza infection are CD8 + effector T cells, a population of cells that is found later in infection (41). In addition, increased levels of this cytokine early during infection can hinder the activation of the antiviral immune response (53), suggesting that the increased levels observed in the WT mice early during infection may be detrimental.…”

Section: Discussionmentioning

confidence: 99%

Contribution of the Purinergic Receptor P2X7 to Development of Lung Immunopathology during Influenza Virus Infection

Leyva-Grado

Ermler

Schotsaert

et al. 2017

mBio

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An exacerbated immune response is one of the main causes of influenza-induced lung damage during infection. The molecular mechanisms regulating the fate of the initial immune response to infection, either as a protective response or as detrimental immunopathology, are not well understood. The purinergic receptor P2X7 is an ionotropic nucleotide-gated ion channel receptor expressed on immune cells that has been implicated in induction and maintenance of excessive inflammation. Here, we analyze the role of this receptor in a mouse model of influenza virus infection using a receptor knockout (KO) mouse strain. Our results demonstrate that the absence of the P2X7 receptor results in a better outcome to influenza virus infection characterized by reduced weight loss and increased survival upon experimental influenza challenge compared to wild-type mice. This effect was not virus strain specific. Overall lung pathology and apoptosis were reduced in virus-infected KO mice. Production of proinflammatory cytokines and chemokines such as interleukin-10 (IL-10), gamma interferon (IFN-γ), and CC chemokine ligand 2 (CCL2) was also reduced in the lungs of the infected KO mice. Infiltration of neutrophils and depletion of CD11b+ macrophages, characteristic of severe influenza virus infection in mice, were lower in the KO animals. Together, these results demonstrate that activation of the P2X7 receptor is involved in the exacerbated immune response observed during influenza virus infection.

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“…TNF-α can be produced by different cell types after influenza infection, including TNF/iNOS-producing DCs (tipDCs) [42], lung epithelial cells [43], and helper T cells and cytotoxic T lymphocytes [44]. TNF-α is considered to be the prototypical proinflammatory cytokine at the “center of the influenza cytokine storm”, escalating the severity of disease in humans with highly pathogenic and pathological influenza infections[45] [46] [47].…”

Section: Cytokines Directly Induced By Viral Infection (Primary Cytokmentioning

confidence: 99%

New fronts emerge in the influenza cytokine storm

2017

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Influenza virus is a significant pathogen in humans and animals with the ability to cause extensive morbidity and mortality. Exuberant immune responses induced following infection have been described as a “cytokine storm”, associated with excessive levels of proinflammatory cytokines and widespread tissue damage. Recent studies have painted a more complex picture of cytokine networks and their contributions to clinical outcomes. While many cytokines clearly inflict immunopathology, others have non-pathological delimited roles in sending alarm signals, facilitating viral clearance, and promoting tissue repair, such as the IL-33 – amphiregulin axis, which plays a key role in resolving some types of lung damage. Recent literature suggests that type 2 cytokines, traditionally thought of as not involved in anti-influenza immunity, may play an important regulatory role. Here we discuss the diverse roles played by cytokines after influenza infection and highlight new, serene features of the cytokine storm, while highlighting the specific functions of relevant cytokines that perform unique immune functions and may have applications for influenza therapy.

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The Effector T Cell Response to Influenza Infection

Cited by 77 publications

References 154 publications

Vaccine efficacy and T helper cell differentiation change with aging

Vaccine efficacy and T helper cell differentiation change with aging

Contribution of the Purinergic Receptor P2X7 to Development of Lung Immunopathology during Influenza Virus Infection

New fronts emerge in the influenza cytokine storm

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