Self-tolerance of mature, peripheral CD4+ T cells in Vb5 transgenic (Tg) mice occurs through two pathways, deletion and T cell receptor (TCR) revision. Both processes are driven by chronic encounter with a peripherally expressed self-antigen encoded by mouse mammary tumor virus (Mtv) 8. Recognition of Mtv-8 expressed by dendritic cells renders CD4+Vb5+ T cells anergic and results in their deletion and the concomitant inversion of the peripheral CD4:CD8 ratio. T cells that chronically recognize Mtv-8 on B cells instead enter the germinal center and undergo TCR revision. During the process of TCR revision, T cells lose Vb5 surface expression, upregulate expression of the lymphocyte-specific recombinase machinery (RAG1, RAG2, and TdT), and rearrange endogenous TCR Vb genes. Deletion of Rag in peripheral T cells blocks TCR revision. Post revision T cells are Vb5- and fail to recognize Mtv-8, yet express a diverse TCRb repertoire and are self-MHC restricted and functional. The goal of this exploratory grant is to place the population of revising T cells in the context of a defined T cell subpopulation of known function. Our previous characterization of T cells in the process of TCR revision hint at a phenotypic overlap with the follicular helper T cell compartment. With this pilot grant, we will determine the relationship between the frequencies of revising T cells and germinal center B and T cells, and determine whether revising T cells bear the phenotypic and functional characteristics of follicular helper T cells. These experiments will help place TCR revision within the larger framework of T cell immunology, and will explore how TCR revision may impact the B cell arm of the adaptive immune response.

Public Health Relevance

T cell receptor revision is a means for inducing self tolerance in mature peripheral T cells, and results in the age-dependent expression of an extrathymically-generated antigen receptor repertoire through gene recombination. Understanding what cell compartment revising T cells occupy, what functions they perform, and what other cell types they interact with will help us understand what risks are inherent in the process of T cell receptor revision and will help place this tolerance pathway within the growing list of mechanisms in place that serve to help prevent T cell driven autoimmunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Ferguson, Stacy E
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University of Washington
Schools of Medicine
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Moguche, Albanus O; Shafiani, Shahin; Clemons, Corey et al. (2015) ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis. J Exp Med 212:715-28
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
Houston Jr, Evan G; Boursalian, Tamar E; Fink, Pamela J (2012) Homeostatic signals do not drive post-thymic T cell maturation. Cell Immunol 274:39-45