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).
| 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) Krüppel-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 |
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