Molecular Mechanisms in TCR Reactivity to Self Ligands

University Of Minnesota Twin Cities, Minneapolis MN

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Abstract

DESCRIPTION (provided by applicant): 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).