Respiratory tract infections induce strong and long-lasting humoral immune responses locally at the site, contributing significantly to immune protection from challenge infection. The mechanisms that induce and control protective local immune responses are currently not fully understood. The study is based on preliminary data in mice that implicate the rapidly induced extrafollicular foci B cell response as source for long-lived humoral immunity in the respiratory tract following influenza virus infection. The objective for this proposal is to identify the mechanisms that regulate this long-term local antibody response to influenza virus in the respiratory tract.
In Specific Aim #1 the differentiation pathways and protective capacity of lung antibody-secreting cells following influenza virus infection will be measured in wildtype mice and in mice that lack formation of germinal centers (SAP-/- mice) or strong extrafollicular foci responses (following inactivated virus delivery) using BLIMP-1 reporter mice and a newly developed system for tracking of influenza hemagglutinin-specific, C12Id-expressing B cells ex vivo.
Specific Aim #2 will study the mechanisms regulating the migration/retention of lung plasma cell precursors to the respiratory tract. They will assess the extent to which migration of virus-specific B cells/plasma cells from regional lymph nodes is required for the establishment of lung tissue plasma cell pools, and using genetic screening and a custom microfluidics device, will identify the integrins and chemokines/receptors responsible for the selective accumulation and/or retention of plasma cells the lung tissue under shear stress.
Specific Aim #3 will use gene expression studies to determine the differentiation stage of plasma cells/precursors in the lung tissue and BrDU labeling studies to identify the mechanisms underlying the longevity of the antibody-secreting cells in the lung. Adoptive transfer studies will assess the requirements for antigen and/or infection-induced inflammatory signals for their maintenance. These studies will provide novel information on the characteristics and the B cell developmental pathways that generate the long-lived humoral immune responses in the respiratory tract, basic knowledge on B cell response regulation that can aid rationale vaccine design.

Public Health Relevance

Protection from infections with influenza virus is contributed at least in part by antibody-secreting cells that establish in the lung following influenza virus infection. This study aims to understand how these cells are generated and what regulates their migration/maintenance in the lung. This basic information will provide potential avenues for rational vaccine design that aims to boost local/mucosal immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085568-02
Application #
8134252
Study Section
Special Emphasis Panel (ZRG1-IMM-E (02))
Program Officer
Hauguel, Teresa M
Project Start
2010-09-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$375,352
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Nguyen, Trang T T; Graf, Beth A; Randall, Troy D et al. (2017) sIgM-Fc?R Interactions Regulate Early B Cell Activation and Plasma Cell Development after Influenza Virus Infection. J Immunol 199:1635-1646
Savage, Hannah P; Yenson, Vanessa M; Sawhney, Sanjam S et al. (2017) Blimp-1-dependent and -independent natural antibody production by B-1 and B-1-derived plasma cells. J Exp Med 214:2777-2794
Nguyen, Trang T T; Kläsener, Kathrin; Zürn, Christa et al. (2017) The IgM receptor Fc?R limits tonic BCR signaling by regulating expression of the IgM BCR. Nat Immunol 18:321-333
Baumgarth, Nicole (2017) A Hard(y) Look at B-1 Cell Development and Function. J Immunol 199:3387-3394
Nguyen, Trang T T; Baumgarth, Nicole (2016) Natural IgM and the Development of B Cell-Mediated Autoimmune Diseases. Crit Rev Immunol 36:163-177
Baumgarth, Nicole (2016) B-1 Cell Heterogeneity and the Regulation of Natural and Antigen-Induced IgM Production. Front Immunol 7:324
Nguyen, Trang T T; Elsner, Rebecca A; Baumgarth, Nicole (2015) Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction. J Immunol 194:1489-502
Waffarn, Elizabeth E; Hastey, Christine J; Dixit, Neha et al. (2015) Infection-induced type I interferons activate CD11b on B-1 cells for subsequent lymph node accumulation. Nat Commun 6:8991
Savage, Hannah P; Baumgarth, Nicole (2015) Characteristics of natural antibody-secreting cells. Ann N Y Acad Sci 1362:132-42
Elsner, Rebecca A; Hastey, Christine J; Olsen, Kimberly J et al. (2015) Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection. PLoS Pathog 11:e1004976

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