A hallmark of vaccination- or natural infection-induced humoral immunity is its longevity. However, there are fundamental gaps in our ability to appropriately program B cell responses, and this has hampered the development of efficacious vaccines for several pathogens including Clostridium difficile-associated disease. Persistent antibody mediated protection against pathogens is conferred by memory B cells that can respond rapidly to new antigen exposure as well as long-lived plasma cells that reside in the bone marrow and secrete specific antibody. NKT cells provide help to B cells, driving memory B cell and plasma cell differentiation and survival and thus enhance protective antibody responses against toxins, bacteria, and viruses. However, the mechanisms by which NKT cells enhance humoral immunity are poorly understood. Our newest data show that distinct NKT functional subsets exert diverse effects on memory B cell and plasma cell differentiation. Our long-term goal is to systematically develop an understanding of the mechanisms by which NKT cells regulate long-lived humoral immunity and use that knowledge to drive the development of new vaccines. The overall objective of this application is to understand how distinct functional subsets of NKT cells in different organs exert diverse effects on the production of C. difficile toxin-specific antibody and differentiation of memory B cells and long-lived plasma cells. We will therefore test the hypothesis that specialized functional subsets of NKT cells in secondary lymphoid organs, liver, and bone marrow differentially regulate antibody production, memory B cell induction and persistence of long-lived plasma cells. To do this, we will pursue three specific aims:
Specific Aim 1 we will identify the mechanism by which NKT cells induce B cell memory.
Specific Aim 2 we will identify the mechanism by which NKT cells enhance survival of plasma cells.
Specific Aim 3 we will identify functional subsets of NKT cells that enhance antibody production. The approach is innovative because it applies the new concept that different NKT functional subsets have distinct effects on different aspects of humoral immunity and because it employs novel tools to measure NKT-driven memory B cell responses. The proposed research is significant because it is expected to expand our understanding of how NKT cells govern the direction, magnitude, and duration of humoral immunity. In doing so, we will provide the basis for new and/or improved vaccines that harness NKT- mediated humoral immunity, and do so in a manner that appropriately directs the fate of responding B cells.

Public Health Relevance

The proposed research is relevant to public health because it will advance our understanding of how B cell differentiation into memory B cells and long-lived antibody- secreting plasma cells is regulated. This will enhance the knowledge base required to prevent infection by several pathogens for which we lack efficacious vaccines. The proposal is therefore relevant to the part of NIH's mission that pertains to obtaining fundamental knowledge that enhances health, prolongs life, and reduces the burden of human illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI078993-06
Application #
8896206
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Miller, Lara R
Project Start
2008-07-01
Project End
2015-07-31
Budget Start
2014-08-04
Budget End
2015-07-31
Support Year
6
Fiscal Year
2014
Total Cost
$403,693
Indirect Cost
$123,810
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
Rampuria, Pragya; Lang, Gillian A; Devera, T Scott et al. (2017) Coordination between T helper cells, iNKT cells, and their follicular helper subsets in the humoral immune response against Clostridium difficile toxin B. J Leukoc Biol 101:567-576
Richer, Martin J; Lang, Mark L; Butler, Noah S (2016) T Cell Fates Zipped Up: How the Bach2 Basic Leucine Zipper Transcriptional Repressor Directs T Cell Differentiation and Function. J Immunol 197:1009-15
Devera, T Scott; Lang, Gillian A; Lanis, Jordi M et al. (2016) Memory B Cells Encode Neutralizing Antibody Specific for Toxin B from the Clostridium difficile Strains VPI 10463 and NAP1/BI/027 but with Superior Neutralization of VPI 10463 Toxin B. Infect Immun 84:194-204
Rampuria, Pragya; Lang, Mark L (2015) CD1d-dependent expansion of NKT follicular helper cells in vivo and in vitro is a product of cellular proliferation and differentiation. Int Immunol 27:253-63
Lang, Mark L (2014) The importance of B cell CD1d expression for humoral immunity. Expert Rev Vaccines 13:1275-8
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
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
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