Live Imaging of Influenza Infection of the Trachea Reveals Dynamic Regulation of CD8+ T Cell Motility by Antigen

Emo, Kris Lambert; Hyun, Young-Min; Reilly, Emma; Barilla, Christopher; Gerber, Scott A.; Fowell, Deborah J.; Kim, Min‐Soo; Topham, David J.

doi:10.1371/journal.ppat.1005881

Cited by 31 publications

(29 citation statements)

References 47 publications

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“…While our early analysis of the cellular phenotype throughout infection suggested that elimination of neutrophils resulted in a delay in the CD8 + T cell response, rather than sustained impairment, we were interested to examine whether the behavior of the cells in vivo would show a similar delay and recovery. In our lab, we previously established a method of imaging virus-specific CD8 + T cells within the trachea[ 37 ]. We recognize that some differences in the kinetics of clearing the infection may result in differences from those observed in the lungs, however, it is known that the virus is cleared from the organ by day 9 in wild type mice.…”

Section: Resultsmentioning

confidence: 99%

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The Effects of Acute Neutrophil Depletion on Resolution of Acute Influenza Infection, Establishment of Tissue Resident Memory (TRM), and Heterosubtypic Immunity

2016

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After disease resolution, a small subset of influenza specific CD8+ T cells can remain in the airways of the lung as a tissue resident memory population (TRM). These cells are critical for protection from subsequent infections with heterosubtypic influenza viruses. Although it is well established that expression of the collagen IV binding integrin alpha 1 is necessary for the retention and maintenance of TRM cells, other requirements allowing them to localize to the airways and persist are less well understood. We recently demonstrated that inhibition of neutrophils or neutrophil derived chemokine CXCL12 during acute influenza virus infection reduces the effector T cell response and affects the ability of these cells to localize to the airways. We therefore sought to determine whether the defects that occur in the absence of neutrophils would persist throughout resolution of the disease and impact the development of the TRM population. Interestingly, the early alterations in the CD8+ T cell response recover by two weeks post-infection, and mice form a protective population of TRM cells. Overall, these observations show that acute neutrophil depletion results in a delay in the effector CD8+ T cell response, but does not adversely impact the development of TRM.

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Section: Resultsmentioning

confidence: 99%

“…Imaging was performed as described in Lambert-Emo, et al . [ 37 ]. Briefly, images were captured using an Olympus FV1000AOM-Multiphoton imaging system in combination with a Spectra-Physics MaiTai-HP Deep See fs Ti:Sa laser system in the University of Rochester Light Microscopy core.…”

Section: Methodsmentioning

confidence: 99%

The Effects of Acute Neutrophil Depletion on Resolution of Acute Influenza Infection, Establishment of Tissue Resident Memory (TRM), and Heterosubtypic Immunity

2016

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“…T cell velocities increased with Ptx, and confinement decreased (Figure 1A-C; Supplemental Figure 1A-C). On day 9 when cell velocities normally increase markedly, but transiently [9] (Supplemental Movie S1), the effects of Ptx slowed the cells and decreased confinement, with the largest fold-changes observed. Overall, the effects of Ptx-mediated inhibition of signaling through GPCRs varies over the course of acute infection.…”

Section: Resultsmentioning

confidence: 99%

“…We reasoned that the changes on day 9 were the result of a significant reduction in signals received from ABC as the virus is cleared [9]. To address this, we re-introduced antigen in the form of soluble SIINFEKL peptides on days 8 and 9.…”

Section: Resultsmentioning

confidence: 99%

Antigen and G-Protein Coupled Receptor signaling differentially control CD8 T cell motility immediately before and after virus clearance in a primary infection

Lambert-Emo

Reilly

Sportiello

et al. 2019

Preprint

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17 In mice, experimental influenza virus infection stimulates CD8 T cell infiltration of the airways.18 Virus is cleared by day 9, and between days 8 and 9 there is an abrupt change in CD8 T cell 19 motility behavior transitioning from low velocity and high confinement on day 8, to high velocity 20 with continued confinement on day 9. We hypothesized that it is loss of virus and/or antigen 21 signals in the context of high chemokine levels that drives the T cells into a rapid surveillance 22 mode. Virus infection induces chemokine production, which may change when the virus is 23 cleared. We therefore sought to examine this period of rapid changes to the T cell environment in 24 the tissue and seek evidence on the roles of peptide-MHC and chemokine receptor interactions.25 Experiments were performed to block G protein coupled receptor (GPCR) signaling with Pertussis 26 toxin (Ptx). Ptx treatment generally reduced cell velocities and mildly increased confinement, 27 except on day 8 when velocity increased and confinement was relieved, suggesting chemokine 28 mediated arrest. Blocking specific peptide-MHC with monoclonal antibody unexpectedly 29 decreased velocities on days 7 through 9, suggesting TCR/peptide-MHC interactions promote 30 cell mobility in the tissue. Together, these results suggest the T cells are engaged with antigen 31 bearing and chemokine producing cells that affect motility in ways that vary with the day after 32 infection. The increase in velocities on day 9 were reversed by addition of specific peptide, 33 consistent with the idea that antigen signals become limiting on day 9 compared to earlier time 34 points. Thus, antigen and chemokine signals act to alternately promote and restrict CD8 T cell 35 motility until the point of virus clearance, suggesting the switch in motility behavior on day 9 may 36 be due to a combination of limiting antigen in the presence of high chemokine signals as the virus 37 is cleared. 39 Introduction40 Influenza viruses infect roughly 12 percent of the population in any given year [1]. This leads to 41 lost productivity, hospitalizations, and deaths. In the 2017-18 season there was a record 80,000 3 42 deaths in the US alone [2]. In 2018-19, the northern hemisphere experienced the longest flu 43 season in over 20 years [3]. Understanding how the immune system controls influenza infection 44 is paramount to the development of improved vaccination strategies and for understanding the 45 disease process itself. Cytotoxic CD8 T cells are responsible for the initial clearance of infected 46 cells, especially in a primary infection when there are no pre-existing antibodies or other types of 47 adaptive immunity [4, 5]. In order to reach the site of infection, the trachea and airway epithelium, 48 the CD8 T cells must traffic through the circulation, exit into the tissue, and migrate within the 49 tissue before crossing into the epithelial surface. There are many things in the tissue 50 microenvironment that the T cells must interact and communicate with, and many feature...

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“…These interactions along with chemokine signals on the endothelium cause the T cells to arrest and undergo transendothelial migration into the infected tissue. CD8 T cells migrate through the space between the blood vessel and airway epithelium and cross the basement membrane of the epithelium to reach the infected epithelial cells (Lambert Emo et al 2016). Mouse studies suggest the CD8 T cells must also have an encounter with APC within the tissue to be retained and exert effector functions (McGill et al 2008).…”

Section: Cd8 + T-cell Responses To Seasonal Influenza Infectionmentioning

confidence: 99%

Immunity to Influenza Infection in Humans

Topham

DeDiego

Nogales

et al. 2019

Cold Spring Harb Perspect Med

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This review discusses the human immune responses to influenza infection with some insights from studies using animal models, such as experimental infection of mice. Recent technological advances in the study of human immune responses have greatly added to our knowledge of the infection and immune responses, and therefore much of the focus is on recent studies that have moved the field forward. We consider the complexity of the adaptive response generated by many sequential encounters through infection and vaccination.

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Live Imaging of Influenza Infection of the Trachea Reveals Dynamic Regulation of CD8+ T Cell Motility by Antigen

Cited by 31 publications

References 47 publications

The Effects of Acute Neutrophil Depletion on Resolution of Acute Influenza Infection, Establishment of Tissue Resident Memory (TRM), and Heterosubtypic Immunity

The Effects of Acute Neutrophil Depletion on Resolution of Acute Influenza Infection, Establishment of Tissue Resident Memory (TRM), and Heterosubtypic Immunity

Antigen and G-Protein Coupled Receptor signaling differentially control CD8 T cell motility immediately before and after virus clearance in a primary infection

Immunity to Influenza Infection in Humans

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