Abstract

Generation of T cell memory is a critical component of protective immunity. While memory T cells normally arise following priming of naove T cells with foreign antigen, a distinct pathway can also generate functional memory T cells - as a consequence of homeostatic proliferation in a lymphopenic environment. Study of memory T cells produced by homeostatic proliferation (""""""""HP memory"""""""" cells) is relevant to understanding the essential requirements for memory T cell differentiation, and also for assessing the relevance of this alternative pathway in establishing protective immunity in immunocompromized individuals. Using mouse models, we recently showed that both """"""""conventional memory"""""""" T cells (i.e. those generated through priming) and HP memory CD8 T cells offer similar protective immunity against a pathogen. However, while experimental models of lymphopenia are well studied, much less is known about HP memory cells produced during natural situations of lymphopenia (in the neonatal period and after acute infections). We explore this in three aims, studying: the function of HP memory CD8 T cells generated in """"""""natural"""""""" lymphopenic environments (Aim 1): the presence and function of antigen specific endogenous HP memory CD8 T cells (Aim 2) and the role of neonatal lymphopenia and endogenous HP CD8 memory T cells in supporting immune reactivity of the young animals (Aim 3). The goal of these studies is to determine whether foreign antigen responsive HP memory CD8 T cells are generated during natural bouts of lymphopenia, and whether they contribute to the adaptive immune response. PUBLIC HEALTH RELEVENCE: Memory T cells are a critical element in immune protection against pathogens. Memory cells are generated as a consequence of immune priming, but are also generated during the response to immuno-deficiency, or lymphopenia, which occurs physiologically during development and also as a consequence of infections. The significance of the proposal is in learning how such """"""""homeostatic"""""""" mechanisms may foster establishment of protective """"""""memory- like"""""""" CD8 T cells system in immunocompromized individuals, including the very young.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI075168-02
Application #
7609195
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Lapham, Cheryl K
Project Start
2008-05-01
Project End
2013-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
2
Fiscal Year
2009
Total Cost
$365,395
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Borges da Silva, Henrique; Beura, Lalit K; Wang, Haiguang et al. (2018) The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Nature 559:264-268
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
Lee, You Jeong; Starrett, Gabriel J; Lee, Seungeun Thera et al. (2016) Lineage-Specific Effector Signatures of Invariant NKT Cells Are Shared amongst ?? 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
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
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, 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
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

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