Our most effective vaccines stimulate long-term neutralizing Ab responses by stimulating the immune system to maintain Ag-specific memory B cells and long-lived Ab-secreting plasma cells. In order to develop more effective Ab-stimulating vaccines in future, we need to improve our understanding of the mechanisms by which humoral immunity is induced and maintained. We reported that activation of CD1d- restricted NKT cells with the CD1d-binding glycolipid 1-Galactosylceramide (1-GC) at the time of immunization with a protein Ag resulted in enhanced Ab responses to that Ag. Since then we have observed that NKT cells enhance Ab recall responses following a secondary booster with Ag. We have also obtained data consistent with the hypothesis that the recall responses are a result of NKT cells enhancing memory B cell induction and plasma cell longevity. Despite this progress there are no current reports on the mechanisms by which NKT cells contribute to induction and maintenance of humoral immunity. Our preliminary data suggest that NKT cells utilize several mechanisms to induce and maintain an effective humoral immune response. These include (i) NKT-derived IL-5 which supports plasma cell induction (ii) NKT-expressed CD154 a ligand for CD40 expressed on B cells and perhaps important for the induction of primary Ab responses and memory B cells (iii) The TNF family member BAFF (B cell-activating factor) that promotes development and survival of plasma cells. In this proposal we will examine the mechanisms by which NKT cells impact humoral immune responses. Hypothesis and Aims: We will test the hypothesis that NKT cell-derived cytokines, CD154 and plasma cell survival factor BAFF contribute substantially to humoral immune responses by supporting the induction and maintenance of the memory B cell and long-lived plasma cell pool.
In Specific Aim 1, we will assess the effects of CD1d-dependent NKT activation and NKT absence on humoral immune responses.
In Specific Aim 2, we will determine how NKT-derived IL-5 and CD154 enhance humoral immune responses.
In Specific Aim 3, we will determine if NKT-derived BAFF influences the induction of long-lived Ag-specific plasma cells. We will elucidate the mechanisms by which NKT cells support and enhance the induction and maintenance of humoral immune responses, thus integrating two previously diverse fields of research and substantially contributing to both. Our findings will be valuable for understanding humoral immunity and may contribute to the design of novel vaccination strategies that incorporate NKT activation.

Public Health Relevance

Most successful vaccines stimulate long-lived humoral immune responses mediated by protective antibody. Despite remarkable progress in understanding the mechanisms by which humoral immunity is induced and sustained, there is much to learn. This is of particular importance if we are to develop novel vaccines in the future against remaining pathogens for which there is no vaccine. We have discovered that activation of NKT cells enhances primary and recall antibody responses. Our data indicate that this is due to increasing the generation of memory B cells, the precursor of antibody-secreting plasma cells and by increasing the persistence of plasma cells. Our project will assess the impact of NKT cells on memory B cell and plasma cell induction and maintenance. We will then conduct mechanistic studies to understand how NKT cells achieve their effects on memory B cells and plasma cells. Our work will advance the understanding of the mechanisms by which NKT cells affect humoral immune responses and may highlight new opportunities to develop novel vaccine strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078993-05
Application #
8417690
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Miller, Lara R
Project Start
2009-02-15
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$302,320
Indirect Cost
$95,028
Name
University of Oklahoma Health Sciences Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Joshi, Sunil K; Lang, Mark L (2013) Fine tuning a well-oiled machine: Influence of NK1.1 and NKG2D on NKT cell development and function. Int Immunopharmacol 17:260-6
Shah, Hemangi B; Joshi, Sunil K; Rampuria, Pragya et al. (2013) BAFF- and APRIL-dependent maintenance of antibody titers after immunization with T-dependent antigen and CD1d-binding ligand. J Immunol 191:1154-63
Lang, Gillian A; Johnson, Amy M; Devera, T Scott et al. (2011) Reduction of CD1d expression in vivo minimally affects NKT-enhanced antibody production but boosts B-cell memory. Int Immunol 23:251-60
Shah, Hemangi B; Joshi, Sunil K; Lang, Mark L (2011) CD40L-null NKT cells provide B cell help for specific antibody responses. Vaccine 29:9132-6
Charles, Elizabeth; Joshi, Sunil; Ash, John D et al. (2010) CD4 T-cell suppression by cells from Toxoplasma gondii-infected retinas is mediated by surface protein PD-L1. Infect Immun 78:3484-92
Joshi, Sunil K; Lang, Gillian A; Larabee, Jason L et al. (2009) Bacillus anthracis lethal toxin disrupts TCR signaling in CD1d-restricted NKT cells leading to functional anergy. PLoS Pathog 5:e1000588
Lang, Mark L (2009) How do natural killer T cells help B cells? Expert Rev Vaccines 8:1109-21