The specificities and numbers of lymphocytes in animals are tightly controlled to avoid autoimmunity and to avoid accumulation of lymphocytesgeneratedduring previous infections. This control can be achieved through the death of autoreactive lymphocytes as consequenceof selection events. Similarly, many lymphocytes that are generated in response to infections die when the infectious agent disappears. The lymphocyte repertoire is also influenced by the ability of lymphocytes to alter their antigen receptor. For example, the antigen receptor expressed by some autoreactive lymphocytes can be modified either by deletion of the genes encoding the offending receptor, or by silencing the action of the autoreactive receptor. At the peak of an immune response against a natural infection, a host can generate pathogen-specific T cell responses that comprise 20-50% of the hosts'total T cell pool. We have now identified a vaccination strategy that is able to generate a similar level of T cell expansion from a purely molecular based vaccine, a result not possible with previously developed vaccine strategies. These high levels of CD8+ T cell expansion can be achieved by the vaccination of a host with antigen in combination with agonists for both the Toll-Like Receptor (TLR) and CD40 pathways (combined TLR/CD40-agonist immunization). We have further identified Type 1 interferon (IFNap) as a central mediator of this synergy in response to certain TLR/CD40- agonist combinations. As IFNap is more often associated with inhibition of virus replication rather than promotion of CD8+ T cell expansion, these studies have identified a potentially novel role for IFNap in promoting adaptive immunity. Most recently, we have observed that both regulatory CD4 cells and dendritic cells expression of TNF ligand superfamily members are critical components by which IFNap influences CD8+ T cell immunity. In the studies proposed here, the mechanism(s) by which IFNap promotes CD8+ T cell expansion and long term protective immunity following combined TLR/CD40-agonist immunization will be determined. Understanding these mechanisms will naturally lead to the development of more potent vaccines against diseases such as HIV, HCV and cancer;diseases whose treatment seems to require the magnitude of cellular immunity that only combined TLR/CD40-agonist immunization is capable of generating.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066121-04
Application #
7745527
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Lapham, Cheryl K
Project Start
2007-01-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$373,909
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
White, Jason T; Cross, Eric W; Kedl, Ross M (2017) Antigen-inexperienced memory CD8+ T cells: where they come from and why we need them. Nat Rev Immunol 17:391-400
Eberlein, Jens; Davenport, Bennett; Nguyen, Tom et al. (2016) Aging promotes acquisition of naive-like CD8+ memory T cell traits and enhanced functionalities. J Clin Invest 126:3942-3960
Pennock, Nathan D; Kedl, Justin D; Kedl, Ross M (2016) T Cell Vaccinology: Beyond the Reflection of Infectious Responses. Trends Immunol 37:170-180
Pritchard, Gretchen Harms; Cross, Eric W; Strobel, Marjorie et al. (2016) Spontaneous partial loss of the OT-I transgene. Nat Immunol 17:471
White, Jason T; Cross, Eric W; Burchill, Matthew A et al. (2016) Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat Commun 7:11291
Burchill, Matthew A; Tamburini, Beth A; Kedl, Ross M (2015) T cells compete by cleaving cell surface CD27 and blocking access to CD70-bearing APCs. Eur J Immunol 45:3140-9
Thompson, Elizabeth A; Liang, Frank; Lindgren, Gustaf et al. (2015) Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Nonhuman Primates. J Immunol 195:1015-24
Kedl, Justin D; Kedl, Ross M (2015) How squalene GLAdly helps generate antigen-specific T cells via antigen-carrying neutrophils and IL-18. Eur J Immunol 45:376-9
Tamburini, Beth A; Burchill, Matthew A; Kedl, Ross M (2014) Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection. Nat Commun 5:3989
Pennock, Nathan D; Gapin, Laurent; Kedl, Ross M (2014) IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization. Proc Natl Acad Sci U S A 111:16472-7

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