Recent data lead to the intriguing conclusion that both immature and mature T-cells have the capacity to make a response to self peptide/MHC ligands. Indeed, these experiments find that such interactions are required for T-cell development and also mature T-cell homeostasis and survival. Furthermore, recent findings show that many but not all naive T-cells can respond, via proliferation and differentiation, toward self peptide/MHC ligands in conditions where total T-cell numbers are low (i.e. in lymphopenic animals). This proliferative process has been called T-cell homeostatic expansion (HME). Such data raise the question of how T-cell survival and HME are regulated to prevent loss of useful T-cell at one extreme and overt autoreactivity at the other. In this proposal, we will explore the nature of the extracellular and intracellular factors which support T-cell survival and T-cell homeostatic expansion. Four components will be studied, the TCR, cytokines, bcl-2 family proteins and a transcription factor, Lung kruppel-like factor (LKLF).
Three aims are proposed. 1. Defining a T-cell's sense of space: HME only occurs in the absence of other T-cells - our hypothesis is that cytokines determine space """"""""perception"""""""" and that the affinity of the TCR for self MHC ligands can influence IL-7 reactivity. 2. Testing bel-2 family members as substitutes for cytokin and/or TCR in homeostatic expansion: Bc1-2 proteins protect against cell death and can substitute for cytokines in T-cell development and survival. We hypothesize that bcl-2 can also substitute for cytokines and/or TCR signals in HME. 3. Role of LKLF in T-cell homeostasis: To better understand LKLF function, we will generate an LKLF transgenic mouse, and test the theory that LKLF is a master regulator of naive T ceil survival and HME. The long-term aims of this application are to understand the way in which useful T-cells are maintained in the body long term and how mature T-cells can be repopulated in cases of T lymphopenia. This has health implications for recovery of the T-cell pool in patients suffering from T lymphopenia due to disease (e.g. AIDS), or therapeutic treatments (such as bone morrow transplant).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI038903-06A1
Application #
6382783
Study Section
Immunobiology Study Section (IMB)
Program Officer
Quill, Helen R
Project Start
1996-07-01
Project End
2006-05-31
Budget Start
2001-07-01
Budget End
2002-05-31
Support Year
6
Fiscal Year
2001
Total Cost
$275,056
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
Jameson, Stephen C; Masopust, David (2018) Understanding Subset Diversity in T Cell Memory. Immunity 48:214-226
Pritchard, Gretchen Harms; Cross, Eric W; Strobel, Marjorie et al. (2016) Spontaneous partial loss of the OT-I transgene. Nat Immunol 17:471
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
Akue, Adovi D; Lee, June-Yong; Jameson, Stephen C (2012) Derivation and maintenance of virtual memory CD8 T cells. J Immunol 188:2516-23
Weinreich, Michael A; Jameson, Stephen C; Hogquist, Kristin A (2011) Postselection thymocyte maturation and emigration are independent of IL-7 and ERK5. J Immunol 186:1343-7
Lee, You Jeong; Jameson, Stephen C; Hogquist, Kristin A (2011) Alternative memory in the CD8 T cell lineage. Trends Immunol 32:50-6
Weinreich, Michael A; Odumade, Oludare A; Jameson, Stephen C et al. (2010) T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells. Nat Immunol 11:709-16
Odumade, Oludare A; Weinreich, Michael A; Jameson, Stephen C et al. (2010) Kr├╝ppel-like factor 2 regulates trafficking and homeostasis of gammadelta T cells. J Immunol 184:6060-6
Xiao, Zhengguo; Casey, Kerry A; Jameson, Stephen C et al. (2009) Programming for CD8 T cell memory development requires IL-12 or type I IFN. J Immunol 182:2786-94

Showing the most recent 10 out of 15 publications