The generation of memory T cells is the end result of a productive immune response. We propose that the survival of just a few effector cells is instructed during the initial activation process. Characterization of this instructional process has been significantly hampered by the inability to identify precisely which primary responder cells will differentiate into memory T cells. Recently we have shown that CD8alpha/alpha expression on a selected subset of CD8aa+ primary effectors uniquely marks the precursors of memory CD8 T cells. This new insight provides for the first time a powerful tool to evaluate the instructional process of CD8 T cell memory formation. In the first Aim of this grant we will define the role of subsets and maturation stages of Dendritic Cells (DC) in generating the CD8alpha/alpha+ memory precursor population. In a second Aim, we will address the role of T cell help in the generation of CTL memory. The contributions of conventional CD4 Th help and help provided by NKT cells will be investigated. In a third Aim we will focus on the CD8 effector T cells themselves, and evaluate the extent to which the quality of the TCR activation signals contributes to the initial selection of CD8alpha/alpha+ memory precursor cells and to the further selection and interclonal competition during repeated antigenic stimulations. Elucidating the initial events that lead to effective memory are extremely important for the design of vaccines and drugs that stimulate optimal immunity against infections and cancers, or treatments that dampen the response in autoimmunity or transplantation. The experiments in this proposal use lymphocytic choriomeningitis virus (LCMV), an arena virus. Understanding the basic mechanism of CDS memory formation to viruses and other pathogenic agents is highly relevant to the biodefense needs facing the United States today.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064584-04
Application #
7373584
Study Section
Special Emphasis Panel (ZRG1-IHD (01))
Program Officer
Palker, Thomas J
Project Start
2005-03-15
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$441,363
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Verstichel, Greet; Vermijlen, David; Martens, Liesbet et al. (2017) The checkpoint for agonist selection precedes conventional selection in human thymus. Sci Immunol 2:
Larange, Alexandre; Cheroutre, Hilde (2016) Retinoic Acid and Retinoic Acid Receptors as Pleiotropic Modulators of the Immune System. Annu Rev Immunol 34:369-94
Vicente-Suarez, I; Larange, A; Reardon, C et al. (2015) Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells. Mucosal Immunol 8:141-51
Davani, Dariush; Pancer, Zeev; Cheroutre, Hilde et al. (2014) Negative selection of self-reactive chicken B cells requires B cell receptor signaling and is independent of the bursal microenvironment. J Immunol 192:3207-17
Mayans, Sofia; Stepniak, Dariusz; Palida, Sakina et al. (2014) ??T cell receptors expressed by CD4(-)CD8??(-) intraepithelial T cells drive their fate into a unique lineage with unusual MHC reactivities. Immunity 41:207-218
Fu, Guo; Casas, Javier; Rigaud, Stephanie et al. (2013) Themis sets the signal threshold for positive and negative selection in T-cell development. Nature 504:441-5
Walker, L J; Marrinan, E; Muenchhoff, M et al. (2013) CD8?? Expression Marks Terminally Differentiated Human CD8+ T Cells Expanded in Chronic Viral Infection. Front Immunol 4:223
Cheroutre, Hilde; Huang, Yujun (2013) Crosstalk between adaptive and innate immune cells leads to high quality immune protection at the mucosal borders. Adv Exp Med Biol 785:43-7
Steinberg, Marcos W; Huang, Yujun; Wang-Zhu, Yiran et al. (2013) BTLA interaction with HVEM expressed on CD8(+) T cells promotes survival and memory generation in response to a bacterial infection. PLoS One 8:e77992
Shui, Jr-Wen; Larange, Alexandre; Kim, Gisen et al. (2012) HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria. Nature 488:222-5

Showing the most recent 10 out of 15 publications