Contemporary Analysis of MHC-Related Immunodominance Hierarchies in the CD8+T Cell Response to Influenza A Viruses

Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection in a high percentage of the population worldwide. CMV induces the strongest and most durable CD8+ T cell response known in human clinical medicine. Due to its unique properties, the virus represents a promising candidate vaccine vector for the induction of persistent cellular immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) expressing an MHC-I restricted epitope from influenza A virus (IAV) H1N1 within the immediate early 2 (ie2) gene. Only mice that were immunized intranasally (i.n.) were capable of controlling IAV infection, despite the greater potency of the intraperitoneally (i.p.) vaccination in inducing a systemic IAV-specific CD8+ T cell response. The protective capacity of the i.n. immunization was associated with its ability to induce IAV-specific tissue-resident memory CD8+ T (CD8TRM) cells in the lungs. Our data demonstrate that the protective effect exerted by the i.n. immunization was critically mediated by antigen-specific CD8+ T cells. CD8TRM cells promoted the induction of IFNγ and chemokines that facilitate the recruitment of antigen-specific CD8+ T cells to the lungs. Overall, our results showed that locally applied MCMV vectors could induce mucosal immunity at sites of entry, providing superior immune protection against respiratory infections.

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Human Influenza A Virus–Specific CD8+ T-Cell Response Is Long-lived

The Journal of Infectious Diseases ◽

10.1093/infdis/jiv018 ◽

2015 ◽

Vol 212 (1) ◽

pp. 81-85 ◽

Cited By ~ 34

Author(s):

Carolien E. van de Sandt ◽

Marine L. B. Hillaire ◽

Martina M. Geelhoed-Mieras ◽

Albert D. M. E. Osterhaus ◽

Ron A. M. Fouchier ◽

...

Keyword(s):

T Cell ◽

Influenza A Virus ◽

Cell Response ◽

Influenza A ◽

Cd8 T Cell ◽

T Cell Response ◽

Human Influenza

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Chronic ethanol exposure selectively inhibits the influenza-specific CD8 T cell response during influenza A virus infection

Alcohol ◽

10.1016/j.alcohol.2013.09.017 ◽

2013 ◽

Vol 47 (7) ◽

pp. 571 ◽

Cited By ~ 1

Author(s):

E.A. Hemann ◽

J.L. McGill ◽

T.J. Waldschmidt ◽

K.L. Legge

Keyword(s):

T Cell ◽

Virus Infection ◽

Influenza A Virus ◽

Cell Response ◽

Influenza A ◽

Cd8 T Cell ◽

Ethanol Exposure ◽

T Cell Response ◽

Chronic Ethanol Exposure ◽

Influenza A Virus Infection

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Plasmacytoid Dendritic Cells Require Direct Infection To Sustain the Pulmonary Influenza A Virus-Specific CD8 T Cell Response

Journal of Virology ◽

10.1128/jvi.02546-15 ◽

2015 ◽

Vol 90 (6) ◽

pp. 2830-2837 ◽

Cited By ~ 6

Author(s):

Emily A. Hemann ◽

Louisa E. Sjaastad ◽

Ryan A. Langlois ◽

Kevin L. Legge

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Influenza A ◽

Cd8 T Cell ◽

T Cell Response ◽

Cross Presentation ◽

Cell Responses ◽

Presentation Pathway

ABSTRACTFollowing influenza A virus (IAV) infection, development of a robust IAV-specific CD8 T cell response is required for clearance of primary infection and enhances memory protection. Following IAV infection, plasmacytoid dendritic cells (pDC) or CD8α+DC regulate pulmonary effector CD8 T cell responses within the lung. Without this DC-T cell interaction, insufficient effector CD8 T cells are maintained in the lungs, leading to enhanced morbidity and mortality. Previous studies have demonstrated that pDC are capable of classical presentation or cross-presentation of IAV antigens and could potentially regulate IAV-specific CD8 T cell responses through either mechanism. Our results demonstrate that pDC from the lungs of donor mice infected with an IAV that is not able to replicate in hematopoietic cells (142t-IAV), unlike donor pDC isolated from the lungs of control infected mice, are not able to rescue the host IAV-specific CD8 T cell response from apoptosis. This indicates that pDC must utilize the direct presentation pathway for this rescue. This inability of pDC from 142t-IAV donors to rescue the IAV-specific CD8 T cell response is not due to differences in the overall ability of 142t-IAV to replicate within the lungs or generate defective viral genomes or to differences in levels of costimulatory molecules required for this interaction. We further demonstrate that bypassing the antigen presentation pathway by coating the 142t-IAV pDC with IAV peptide epitopes restores their ability to rescue the IAV-specific CD8 T cell response.IMPORTANCEIAV continues to be a global health burden, infecting 5 to 20% of the global population annually. Continued investigation into the mechanisms that mediate protective immune responses against IAV is important to improving current vaccination and antiviral strategies antagonistic toward IAV. Our findings presented herein demonstrate a key requirement for pDC promotion of effector CD8 T cell survival: that rather than utilizing cross-presentation, pDC must be infected and utilize the endogenous pathway for presentation of antigens to CD8 T cells duringin vivoIAV infections. This suggests that targeting presentation via the endogenous pathway in pDC could be important for the development of unique antiviral cellular therapies.

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Modification of Cytotoxic T-Cell Response Patterns by Administration of Hemagglutinin-Specific Monoclonal Antibodies to Mice Infected with Influenza A Viruses

Hybridoma ◽

10.1089/hyb.1.1982.1.149 ◽

1982 ◽

Vol 1 (2) ◽

pp. 149-159 ◽

Cited By ~ 2

Author(s):

NEIL GREENSPAN ◽

PETER C. DOHERTY

Keyword(s):

Monoclonal Antibodies ◽

T Cell ◽

Cell Response ◽

Influenza A ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Response Patterns ◽

Influenza A Viruses

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Chronic Ethanol Exposure Selectively Inhibits the Influenza-Specific CD8 T Cell Response During Influenza A Virus Infection

Alcoholism Clinical and Experimental Research ◽

10.1111/acer.12522 ◽

2014 ◽

Vol 38 (9) ◽

pp. 2403-2413 ◽

Cited By ~ 8

Author(s):

Emily A. Hemann ◽

Jodi L. McGill ◽

Kevin L. Legge

Keyword(s):

T Cell ◽

Virus Infection ◽

Influenza A Virus ◽

Cell Response ◽

Influenza A ◽

Cd8 T Cell ◽

Ethanol Exposure ◽

T Cell Response ◽

Chronic Ethanol Exposure ◽

Influenza A Virus Infection

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Hemagglutinin-specific complement-dependent antibody response to influenza infection

Journal of Experimental Medicine ◽

10.1084/jem.147.1.265 ◽

1978 ◽

Vol 147 (1) ◽

pp. 265-270 ◽

Cited By ~ 15

Author(s):

MW Verbonitz ◽

FA Ennis ◽

JT Hicks ◽

P Albrecht

Keyword(s):

T Cell ◽

Antibody Response ◽

Cell Response ◽

Influenza A ◽

Present Report ◽

Influenza Infection ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Target Cells ◽

Influenza A Viruses

The host defense response to influenza infection is complex. Specific humoral antibodies develop to the strain-specific surface antigens, the hemagglutinin and the neuraminidase, and to the internal antigens (matrix and nucleoprotein) which are common to all influenza A viruses (1). Antibodies to the hemagglutinin, which is the major surface antigen, neutralize viral infectivity (2). In addition to antibodies which have been detected against virion antigens, a cytotoxic T-cell response with specificity against the viral hemagglutinin on influenza-infected target cells (3-5) has been recently described. A more cross-reactive cytotoxic T-cell response has also been observed when a nonpermissively infected target cell is used in cytotoxicity assays (6,7). The present report describes the development during influenza infection and after vaccination of a cytolytic humoral antibody response which is directed against the hemagglutinin on infected target cells. This antibody-mediated lysis of infected cells in complement dependent, as has been reported with other virus infections (8-11).

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Broad-Based Influenza-Specific CD8+ T Cell Response without the Typical Immunodominance Hierarchy and Its Potential Implication

Viruses ◽

10.3390/v13061080 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1080

Author(s):

Miaojuan Huang ◽

Rong Xu ◽

Cristina Triffon ◽

Nicole Mifsud ◽

Weisan Chen

Keyword(s):

T Cell ◽

Cell Response ◽

Influenza A ◽

Epitope Prediction ◽

Cd8 T Cell ◽

T Cell Response ◽

Potential Implication ◽

Allelic Differences ◽

Screen Approach ◽

The Impact

Syngeneic murine systems have pre-fixed MHC, making them an imperfect model for investigating the impact of MHC polymorphism on immunodominance in influenza A virus (IAV) infections. To date, there are few studies focusing on MHC allelic differences and its impact on immunodominance even though it is well documented that an individual’s HLA plays a significant role in determining immunodominance hierarchy. Here, we describe a broad-based CD8+ T cell response in a healthy individual to IAV infection rather than a typical immunodominance hierarchy. We used a systematic antigen screen approach combined with epitope prediction to study such a broad CD8+ T cell response to IAV infection. We show CD8+ T cell responses to nine IAV proteins and identify their minimal epitope sequences. These epitopes are restricted to HLA-B*44:03, HLA-A*24:02 and HLA-A*33:03 and seven out of the nine epitopes are novel (NP319–330#, M1124–134, M27–15, NA337–346, PB239–49, HA445–453 and NS1195–203). Additionally, most of these novel epitopes are highly conserved among H1N1 and H3N2 strains that circulated in Australia and other parts of the world.

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