Mouse Models Reveal Role of T-Cytotoxic and T-Reg Cells in Immune Response to Influenza: Implications for Vaccine Design

Immunopathologic examination of the lungs of mouse models of experimental influenza virus infection provides new insights into the immune response in this disease. First, there is rapidly developing perivascular and peribronchial infiltration of the lung with T-cells. This is followed by invasion of T-cells into the bronchiolar epithelium, and separation of epithelial cells from each other and from the basement membrane leading to defoliation of the bronchial epithelium. The intraepithelial reaction may involve either CD8 or CD4 T-cytotoxic cells and is analogous to a viral exanthema of the skin, such as measles and smallpox, which occur when the immune response against these infections is activated and the infected cells are attacked by T-cytotoxic cells. Then there is formation of B-cell follicles adjacent to bronchi, i.e., induced bronchial associated lymphoid tissue (iBALT). iBALT reacts like the cortex of a lymph node and is a site for a local immune response not only to the original viral infection, but also related viral infections (heterologous immunity). Proliferation of Type II pneumocytes and/or terminal bronchial epithelial cells may extend into the adjacent lung leading to large zones filled with tumor-like epithelial cells. The effective killing of influenza virus infected epithelial cells by T-cytotoxic cells and induction of iBALT suggests that adding the induction of these components might greatly increase the efficacy of influenza vaccination.

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Exogenous Interleukin-33 Contributes to Protective Immunity via Cytotoxic T-Cell Priming against Mucosal Influenza Viral Infection

Viruses ◽

10.3390/v11090840 ◽

2019 ◽

Vol 11 (9) ◽

pp. 840 ◽

Cited By ~ 1

Author(s):

Chae Won Kim ◽

Hye Jee Yoo ◽

Jang Hyun Park ◽

Ji Eun Oh ◽

Heung Kyu Lee

Keyword(s):

Immune Response ◽

Influenza Virus ◽

T Cell ◽

Viral Infections ◽

Influenza Infection ◽

Influenza Virus Infection ◽

Respiratory Illness ◽

Cytotoxic T Cell ◽

Antiviral Immune Response ◽

Cytotoxic T Cell Responses

Influenza is an infectious respiratory illness caused by the influenza virus. Though vaccines against influenza exist, they have limited efficacy. To additionally develop effective treatments, there is a need to study the mechanisms of host defenses from influenza viral infections. To date, the mechanism by which interleukin (IL)-33 modulates the antiviral immune response post-influenza infection is unclear. In this study, we demonstrate that exogenous IL-33 enhanced antiviral protection against influenza virus infection. Exogenous IL-33 induced the recruitment of dendritic cells, increased the secretion of pro-inflammatory cytokine IL-12, and promoted cytotoxic T-cell responses in the local microenvironment. Thus, our findings suggest a role of exogenous IL-33 in the antiviral immune response against influenza infection.

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Flow Cytometric and Cytokine ELISpot Approaches To Characterize the Cell-Mediated Immune Response in Ferrets following Influenza Virus Infection

Journal of Virology ◽

10.1128/jvi.01001-16 ◽

2016 ◽

Vol 90 (17) ◽

pp. 7991-8004 ◽

Cited By ~ 18

Author(s):

Anthony DiPiazza ◽

Katherine Richards ◽

Frances Batarse ◽

Laura Lockard ◽

Hui Zeng ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Influenza Virus ◽

T Cell ◽

Virus Infection ◽

Influenza Infection ◽

Influenza Virus Infection ◽

Flow Cytometric ◽

Cell Mediated Immune Response ◽

Mhc Locus

ABSTRACTInfluenza virus infections represent a significant socioeconomic and public health burden worldwide. Although ferrets are considered by many to be ideal for modeling human responses to influenza infection and vaccination, efforts to understand the cellular immune response have been severely hampered by a paucity of standardized procedures and reagents. In this study, we developed flow cytometric and T cell enzyme-linked immunosorbent spot (ELISpot) approaches to characterize the leukocyte composition and antigen-specific T cell response within key lymphoid tissues following influenza virus infection in ferrets. Through a newly designed and implemented set of serological reagents, we used multiparameter flow cytometry to directly quantify the frequency of CD4+and CD8+T cells, Ig+B cells, CD11b+myeloid-derived cells, and major histocompatibility complex (MHC) class II-positive antigen-presenting cells (APCs) both prior to and after intranasal infection with A/California/04/09 (H1N1). We found that the leukocyte composition was altered at 10 days postinfection, with notable gains in the frequency of T cells and myeloid cells within the draining lymph node. Furthermore, these studies revealed that the antigen specificity of influenza virus-reactive CD4 and CD8 T cells was very broad, with recognition of the viral HA, NA, M1, NS1, and NP proteins, and that total reactivity to influenza virus postinfection represented approximately 0.1% of the circulating peripheral blood mononuclear cells (PBMC). Finally, we observed distinct patterns of reactivity between individual animals, suggesting heterogeneity at the MHC locus in ferrets within commercial populations, a finding of considerable interest in efforts to move the ferret model forward for influenza vaccine and challenge studies.IMPORTANCEFerrets are an ideal animal model to study transmission, diseases, and vaccine efficacies of respiratory viruses because of their close anatomical and physiological resemblances to humans. However, a lack of reagents has limited our understanding of the cell-mediated immune response following infection and vaccination. In this study, we used cross-reactive and ferret-specific antibodies to study the leukocyte composition and antigen-specific CD4 and CD8 T cell responses following influenza A/California/04/09 (H1N1) virus infection. These studies revealed strikingly distinct patterns of reactivity between CD4 and CD8 T cells, which were overlaid with differences in protein-specific responses between individual animals. Our results provide a first, in-depth look at the T cell repertoire in response to influenza infection and suggest that there is considerable heterogeneity at the MHC locus, which is akin to that in humans and an area of intense research interest.

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Inhibition of indoleamine 2,3-dioxygenase enhances the T-cell response to influenza virus infection

Journal of General Virology ◽

10.1099/vir.0.053124-0 ◽

2013 ◽

Vol 94 (7) ◽

pp. 1451-1461 ◽

Cited By ~ 34

Author(s):

Julie M. Fox ◽

Leo K. Sage ◽

Lei Huang ◽

James Barber ◽

Kimberly D. Klonowski ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Influenza Virus ◽

T Cell ◽

Virus Infection ◽

Cell Response ◽

Influenza Virus Infection ◽

T Cell Response ◽

Th17 Response ◽

Indoleamine 2,3 Dioxygenase

Influenza infection induces an increase in the level of indoleamine 2,3-dioxygenase (IDO) activity in the lung parenchyma. IDO is the first and rate-limiting step in the kynurenine pathway where tryptophan is reduced to kynurenine and other metabolites. The depletion of tryptophan, and production of associated metabolites, attenuates the immune response to infection. The impact of IDO on the primary immune response to influenza virus infection was determined using the IDO inhibitor 1-methyl-d,l-tryptophan (1MT). C57BL/6 mice treated with 1MT and infected with A/HKx31 influenza virus had increased numbers of activated and functional CD4+ T-cells, influenza-specific CD8+ T-cells and effector memory cells in the lung. Inhibition of IDO increased the Th1 response in CD4+ T-cells as well as enhanced the Th17 response. These studies show that inhibition of IDO engenders a more robust T-cell response to influenza virus, and suggests an approach for enhancing the immune response to influenza vaccination by facilitating increased influenza-specific T-cell response.

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

mBio ◽

10.1128/mbio.00229-17 ◽

2017 ◽

Vol 8 (2) ◽

Cited By ~ 16

Author(s):

Victor H. Leyva-Grado ◽

Megan E. Ermler ◽

Michael Schotsaert ◽

Ma G. Gonzalez ◽

Virginia Gillespie ◽

...

Keyword(s):

Immune Response ◽

Influenza Virus ◽

Virus Infection ◽

Host Defense ◽

Purinergic Receptors ◽

Viral Infections ◽

Purinergic Receptor ◽

Influenza Virus Infection ◽

Lung Pathology ◽

Wild Type

ABSTRACT 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. IMPORTANCE A hallmark of influenza virus infection is the development of lung pathology induced by an exacerbated immune response. The mechanisms shared by the antiviral host defense required for viral clearance and those required for development of immunopathology are not clearly understood. Purinergic receptors, and in particular the purinergic receptor P2X7 (P2X7r), are involved in activation of the immune response. We used mice lacking the P2X7r (P2X7r KO mice) to better understand the mechanisms that lead to development of lung pathology during influenza virus infection. In our studies, we observed that P2X7r KO mice developed less lung immunopathology and had better survival than the wild-type mice. These results implicate P2X7r in the induction of an exacerbated local immune response to influenza virus and help us to better understand the mechanisms leading to the lung immunopathology observed during severe viral infections. IMPORTANCE A hallmark of influenza virus infection is the development of lung pathology induced by an exacerbated immune response. The mechanisms shared by the antiviral host defense required for viral clearance and those required for development of immunopathology are not clearly understood. Purinergic receptors, and in particular the purinergic receptor P2X7 (P2X7r), are involved in activation of the immune response. We used mice lacking the P2X7r (P2X7r KO mice) to better understand the mechanisms that lead to development of lung pathology during influenza virus infection. In our studies, we observed that P2X7r KO mice developed less lung immunopathology and had better survival than the wild-type mice. These results implicate P2X7r in the induction of an exacerbated local immune response to influenza virus and help us to better understand the mechanisms leading to the lung immunopathology observed during severe viral infections.

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Resistance to and Recovery from Lethal Influenza Virus Infection in B Lymphocyte–deficient Mice

Journal of Experimental Medicine ◽

10.1084/jem.186.12.2063 ◽

1997 ◽

Vol 186 (12) ◽

pp. 2063-2068 ◽

Cited By ~ 173

Author(s):

Mary Beth Graham ◽

Thomas J. Braciale

Keyword(s):

Immune Response ◽

T Cells ◽

Influenza Virus ◽

Virus Infection ◽

B Cell ◽

B Lymphocyte ◽

Influenza Infection ◽

Influenza Virus Infection ◽

Effector T Cells ◽

Deficient Mice

In the adaptive immune response to most viruses, both the cellular and humoral arms of the immune system play complementary roles in eliminating virus and virus-infected cells and in promoting recovery. To evaluate the relative contribution of CD4+ and CD8+ effector T lymphocytes in virus clearance and recovery, we have examined the host response to lethal type A influenza virus infection in B lymphocyte–deficient mice with a targeted disruption in the immunoglobulin mu heavy chain. Our results indicate that naive B cell–deficient mice have a 50– 100-fold greater susceptibility to lethal type A influenza virus infection than do wild type mice. However, after priming with sublethal doses of influenza, immune B cell–deficient animals show an enhanced resistance to lethal virus infection. This finding indicates that an antibody-independent immune-mediated antiviral mechanism accounts for the increased resistance to lethal virus challenge. To assess the contribution of influenza-specific CD4+ and CD8+ effector T cells in this process, defined clonal populations of influenza-specific CD4+ and CD8+ effector T cells were adoptively transferred into lethally infected B cell–deficient mice. Cloned CD8+ effectors efficiently promoted recovery from lethal infection, whereas cloned CD4+ T cells conferred only partial protection. These results suggest that memory T lymphocytes can act independently of a humoral immune response in order to confer resistance to influenza infection in immune individuals. The potential implications of these results for vaccination against human influenza infection are discussed.

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Immune response to influenza vaccine and frequency of influenza virus infection in patients with inflammatory bowel disease on maintenance immunosuppressive therapy

Zeitschrift für Gastroenterologie ◽

10.1055/s-0033-1347455 ◽

2013 ◽

Vol 51 (05) ◽

Author(s):

A Bálint ◽

K Farkas ◽

G Terhes ◽

É Kunstár ◽

E Urbán ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Immune Response ◽

Influenza Virus ◽

Virus Infection ◽

Influenza Vaccine ◽

Immunosuppressive Therapy ◽

Bowel Disease ◽

Influenza Virus Infection ◽

Inflammatory Bowel

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Differential Mucin Expression by Respiratory Syncytial Virus and Human Metapneumovirus Infection in Human Epithelial Cells

Mediators of Inflammation ◽

10.1155/2015/347292 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Ma. Del Rocío Baños-Lara ◽

Boyang Piao ◽

Antonieta Guerrero-Plata

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

Epithelial Cells ◽

Viral Infections ◽

Human Metapneumovirus ◽

Human Epithelial Cells ◽

Mucin Expression ◽

Rsv Infection ◽

Syncytial Virus ◽

Tract Disease

Mucins (MUC) constitute an important component of the inflammatory and innate immune response. However, the expression of these molecules by respiratory viral infections is still largely unknown. Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two close-related paramyxoviruses that can cause severe low respiratory tract disease in infants and young children worldwide. Currently, there is not vaccine available for neither virus. In this work, we explored the differential expression of MUC by RSV and hMPV in human epithelial cells. Our data indicate that the MUC expression by RSV and hMPV differs significantly, as we observed a stronger induction of MUC8, MUC15, MUC20, MUC21, and MUC22 by RSV infection while the expression of MUC1, MUC2, and MUC5B was dominated by the infection with hMPV. These results may contribute to the different immune response induced by these two respiratory viruses.

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