Memory CD8+ T cells provide essential specific immunity against previously encountered antigens, and formation of such cells is a fundamental goal of vaccination. Our data show that the pre-immune population of CD8 T cells contains cells with memory-like properties, which we call "Homeostatic memory" (HM) cells. In this proposal we will test how this population of T cells contributes to primary immune responses. Building on our previous data, we will conduct two aims. 1) how the HM pool responds to pathogens early during an immune response, and how these cells may affect pathogen growth or immunopathology that can arise during immune responses. We will also extend data suggesting HM cells differ qualitatively from "na?ve" cells in their response to antigen. 2) This aim extends preliminary data suggesting the cytokine IL-4 plays an unexpected role in controlling CD8 T cell responses. We will assess the function of IL- 4 in controlling memory CD8 T cell maintenance, and build on our preliminary data showing that IL-4 supports the CD8 response to pathogens, by determining the stage at which IL-4 mediates its effects.

Public Health Relevance

T cells make up a key part of the immune system, helping to eliminate infections. Vaccines are designed to make memory T cells which remember microbial components and so stop pathogens (damaging infectious agents) early after an infection. Our research has shown that there are memory T cells specific for pathogens present in the immune system even before an animal has been vaccinated - we wish to understand how these cells may offer natural immunity, giving a measure of resistance to pathogens one has never encountered before, and also how these pre-existing memory cells may enhance immune memory after infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI075168-06A1
Application #
8502797
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Kelly, Halonna R
Project Start
2008-05-01
Project End
2017-04-30
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
6
Fiscal Year
2013
Total Cost
$357,200
Indirect Cost
$122,200
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Lee, You Jeong; Starrett, Gabriel J; Lee, Seungeun Thera et al. (2016) Lineage-Specific Effector Signatures of Invariant NKT Cells Are Shared amongst γδ T, Innate Lymphoid, and Th Cells. J Immunol 197:1460-70
Beura, Lalit K; Hamilton, Sara E; Bi, Kevin et al. (2016) Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532:512-6
Renkema, Kristin R; Lee, June-Yong; Lee, You Jeong et al. (2016) IL-4 sensitivity shapes the peripheral CD8+ T cell pool and response to infection. J Exp Med 213:1319-29
Takada, Kensuke; Van Laethem, Francois; Xing, Yan et al. (2015) TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8(+) T cells. Nat Immunol 16:1069-76
Lee, You Jeong; Wang, Haiguang; Starrett, Gabriel J et al. (2015) Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response. Immunity 43:566-78
Hogquist, Kristin A; Jameson, Stephen C (2014) The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function. Nat Immunol 15:815-23
Lee, June-Yong; Hamilton, Sara E; Akue, Adovi D et al. (2013) Virtual memory CD8 T cells display unique functional properties. Proc Natl Acad Sci U S A 110:13498-503
Olson, Janelle A; McDonald-Hyman, Cameron; Jameson, Stephen C et al. (2013) Effector-like CD8⁺ T cells in the memory population mediate potent protective immunity. Immunity 38:1250-60
Lee, You Jeong; Holzapfel, Keli L; Zhu, Jinfang et al. (2013) Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat Immunol 14:1146-54
Akue, Adovi D; Lee, June-Yong; Jameson, Stephen C (2012) Derivation and maintenance of virtual memory CD8 T cells. J Immunol 188:2516-23

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