The investigator has established B6 V-beta-5 transgenic (Tg) mice as a model system for studying tolerance among mature peripheral CD4+ and CD8+ T-cells. In these animals, an unknown tolerogen drives mature CD8+ T-cells into a CD8 low V-beta, B5low deletional compartment. CD8low cells are defective in their proliferative capacity but can secrete IFN-gamma. They have recently succeeded in generating a synchronized population of CD8lowTCR1ow cells in alpha beta TCR Tg animals by repetitive priming with agonist peptide-expressing splenocytes.
In Specific Aim 1, they will use this experimentally-generated population to define deficiencies in TCR-mediated signaling that contribute to the low proliferative capacity of these deletional intermediates.
In Specific Aim 2, they will determine whether antigen encounter under conditions of limited T-cell help facilitates the generation of CD81owTCRlow cells. The final two aims are based on tolerance mechanisms that operate on the population of mature peripheral CD4+V-beta-5+ T-cells in V-beta-5 Tg mice. These cells interact with a tolerogen encoded by an endogenous mouse mammary tumor virus and are driven along one of two pathways. Cells may be rendered anergic and deleted, a process that results in the inversion of the CD4:CD8 ratio in the periphery of V beta5 Tg mice. Alternatively, cells may be triggered to reexpress their recombination machinery (including RAG genes) and undergo receptor revision by tapping into the endogenous TCR beta chain repertoire. Such cells become V-beta-5 TCR beta endo CD4+ T-cells capable of receiving activation signals through their newly expressed TCRs. The overall goal of Specific Aim 3 is to generate a synchronized population of tagged RAG+CD4+ cells to explore the origin, frequency, and function of this unusual cell compartment. The experiments proposed under Aim 4 are designed to uncover the mechanism of the loss of Vbeta 5 surface expression by CD4+ V-beta-5- T-cells, and to explore the intracellular signals that trigger RAG re-expression. Completion of the proposed experiments will broaden our understanding of the tolerance mechanisms operating on mature peripheral T-cells and further our appreciation of the processes that shape the expressed TCR repertoire in aging individuals. This work will explore the pathways available to T-cells once they have encountered a tolerogen, and will increase our knowledge of the tolerance mechanisms that occasionally fail, thereby causing autoimmune disease.
| Higdon, Lauren E; Deets, Katherine A; Friesen, Travis J et al. (2014) Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions. Proc Natl Acad Sci U S A 111:5652-7 |
| Simmons, Kalynn B; Wubeshet, Maramawit; Ames, Kristina T et al. (2012) Modulation of TCR? surface expression during TCR revision. Cell Immunol 272:124-9 |
| Hale, J Scott; Nelson, Lisa T; Simmons, Kalynn B et al. (2011) Bcl-2-interacting mediator of cell death influences autoantigen-driven deletion and TCR revision. J Immunol 186:799-806 |
| Hale, J Scott; Frock, Richard L; Mamman, Sara A et al. (2010) Cell-extrinsic defective lymphocyte development in Lmna(-/-) mice. PLoS One 5:e10127 |
| Hale, J Scott; Wubeshet, Maramawit; Fink, Pamela J (2010) TCR revision generates functional CD4+ T cells. J Immunol 185:6528-34 |
| Hale, J Scott; Ames, Kristina T; Boursalian, Tamar E et al. (2010) Cutting Edge: Rag deletion in peripheral T cells blocks TCR revision. J Immunol 184:5964-8 |
| Hale, J Scott; Fink, Pamela J (2010) T-cell receptor revision: friend or foe? Immunology 129:467-73 |
| Hendricks, Deborah W; Fink, Pamela J (2009) Uneven colonization of the lymphoid periphery by T cells that undergo early TCR{alpha} rearrangements. J Immunol 182:4267-74 |
| Zehn, Dietmar; Bevan, Michael J; Fink, Pamela J (2007) Cutting edge: TCR revision affects predominantly Foxp3 cells and skews them toward the Th17 lineage. J Immunol 179:5653-7 |
| Cooper, Cristine J; Turk, Gail L; Sun, Mingyi et al. (2004) Cutting edge: TCR revision occurs in germinal centers. J Immunol 173:6532-6 |
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