In lymphocytes, signals from antigen, cytokine, and innate immune receptors cause immediate, transient activation of NF-:B through the canonical pathway by triggering IkB degradation. A second, non-canonical or "alternative" NF-kB pathway has been described downstream of some members of the TNFR family. Slow, sustained activation of NF-kB through this IkB-independent, NIK-dependent non-canonical pathway governs the formation of secondary lymphoid organs (downstream of LT2R) and determines the fate of B cells (downstream of BAFFR). Almost nothing is known of the role of the non-canonical NF-kB pathway in T cell function, although T cells express a number of costimulatory TNFR family members, including OX40, 4-1BB, CD27, GITR, CD30, and HVEM, that have been shown to activate the non-canonical pathway in transfected cell lines, and that are known to provide essential signals for function and survival of activated T cells after antigen recognition. The working hypothesis of this proposal is that sustained activation of NF-kB through the non-canonical pathway downstream of these TNFR family members is necessary for induction and maintenance of expression of the cytokines, cytokine receptors, and anti-apoptotic proteins that allow T cells to survive and function as differentiated effector and memory cells. The proposed experiments are designed to determine whether the non-canonical pathway is activated downstream of the costimulatory TNFR family members in T cells, whether it is necessary for the costimulatory activity of TNFR family members in vivo, and whether independent activation of that pathway mimics some of the costimulatory activities of the TNFR family members, including blocking the function of regulatory T cells.

Public Health Relevance

This grant application proposes to test the idea that a particular intracellular signaling pathway (the non- canonical NF-kB pathway) is necessary in T cells after they see their antigen to allow them to survive and function. Activation of this pathway in T cells could serve as an early biomarker for effective vaccines and a method to reverse T cell unresponsiveness in chronic infections and cancer immunotherapy. Inhibition of this pathway by drugs acting specifically on enzymes in this pathway (IKK1 and/or NIK) has the potential to block ongoing immune reactions that are dependent on internal danger signals resulting from inflammation and tissue damage, such as allergy, autoimmune disease, transplant rejection, and graft-versus-host disease, without blocking immunity to infectious agents driven by antigen receptors and innate receptors for microbial products through a related pathway (the canonical NF-kB pathway) and other signaling pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI092080-02
Application #
8261672
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Mallia, Conrad M
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$385,000
Indirect Cost
$135,000
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Thauland, Timothy J; Koguchi, Yoshinobu; Dustin, Michael L et al. (2014) CD28-CD80 interactions control regulatory T cell motility and immunological synapse formation. J Immunol 193:5894-903
Rowe, Alexander M; Murray, Susan E; Raue, Hans-Peter et al. (2013) A cell-intrinsic requirement for NF-*B-inducing kinase in CD4 and CD8 T cell memory. J Immunol 191:3663-72
Murray, Susan E; Toren, Katelynne Gardner; Parker, David C (2013) Peripheral CD4(+) T-cell tolerance is induced in vivo by rare antigen-bearing B cells in follicular, marginal zone, and B-1 subsets. Eur J Immunol 43:1818-27
Dillon, Tara J; Takahashi, Maho; Li, Yanping et al. (2013) B-Raf is required for positive selection and survival of DP cells, but not for negative selection of SP cells. Int Immunol 25:259-69
Murray, Susan E; Polesso, Fanny; Rowe, Alexander M et al. (2011) NF-ýýBýýýinducing kinase plays an essential T cellýýýintrinsic role in graft-versus-host disease and lethal autoimmunity in mice. J Clin Invest 121:4775-86