In this project we propose to determine the role of candidate G protein-coupled receptors (GPCRs) in enforcing deletion of developing auto-reactive T cells in the thymus. In order for T cells to recognize and respond to the wide array of pathogens encountered throughout life, each cell expresses a unique antigen receptor, the T cell receptor (TCR), that is capable of recognizing and responding to individual pathogens. These vastly diverse receptors are generated by random and imprecise rearrangements of gene segments encoding the TCR. Unfortunately, this random recombination process also yields autoreactive TCRs that could induce autoimmune diseases. To prevent overt autoimmunity, developing T cells are educated in the thymus through interactions with thymic stromal cells: thymocytes expressing overtly autoreactive TCRs are induced to undergo apoptosis. This process of thymic self-tolerance induction is referred to as central tolerance. Central tolerance i imposed largely within the interior, medullary region of the thymus, where thymocytes encounter a wide array of self-antigens expressed on stromal cells, namely dendritic cells and/or medullary thymic epithelial cells. It is critical that developing thymocytes enter the medulla and interact with stromal cells therein to eliminate autoreactive cells. From studies of Autoimmune Polyglandular Syndrome-I patients along with mouse models of this disorder, we know that if central tolerance induction in the medulla is impaired, multi-organ autoimmunity ensues. Based on our previous studies, GPCR signaling is required for thymocyte medullary entry. In this proposal, the role of candidate GPCRs in promoting medullary entry and self-tolerance will be evaluated. Using 2-photon microscopy, live thymocytes deficient for candidate GPCRs will be imaged to determine whether their ability to enter the medulla or to interact with medullary stromal cells is impaired. In a complementary set of traditional immunological approaches, murine models deficient for candidate GPCRs will be tested for overt autoimmunity, as well as for an inability to induce central tolerance to model medullary self- antigens. Finally, unbiased gain-of-function screens will identify additional molecular candidates that promote thymocyte medullary entry and self-tolerance. These studies will illuminate molecular mechanisms that promote thymocyte migration into the medulla and interactions with medullary stromal cells to promote central tolerance, thus broadening our understanding of the etiology of autoimmune diseases.
Autoimmunity occurs when self-reactive lymphocytes fail to succumb to normal tolerance mechanisms. For developing T lymphocytes, self-tolerance is induced in the central region of the thymus, the thymic medulla. Herein, we propose to identify molecular mechanisms that guide developing T cells into the thymic medulla to delete auto-reactive cells before they induce autoimmune diseases.
|Lancaster, Jessica N; Li, Yu; Ehrlich, Lauren I R (2018) Chemokine-Mediated Choreography of Thymocyte Development and Selection. Trends Immunol 39:86-98|
|Hu, Zicheng; Lancaster, Jessica N; Ehrlich, Lauren I R et al. (2018) Detecting T Cell Activation Using a Varying Dimension Bayesian Model. J Appl Stat 45:697-713|
|Thyagarajan, Hiran M; Lancaster, Jessica N; Lira, Sergio A et al. (2018) CCR8 is expressed by post-positive selection CD4-lineage thymocytes but is dispensable for central tolerance induction. PLoS One 13:e0200765|
|Ki, Sanghee; Thyagarajan, Hiran M; Hu, Zicheng et al. (2017) EBI2 contributes to the induction of thymic central tolerance in mice by promoting rapid motility of medullary thymocytes. Eur J Immunol 47:1906-1917|
|Hu, Zicheng; Li, Yu; Van Nieuwenhuijze, Annemarie et al. (2017) CCR7 Modulates the Generation of Thymic Regulatory T Cells by Altering the Composition of the Thymic Dendritic Cell Compartment. Cell Rep 21:168-180|
|Lancaster, Jessica N; Ehrlich, Lauren I R (2017) Analysis of Thymocyte Migration, Cellular Interactions, and Activation by Multiphoton Fluorescence Microscopy of Live Thymic Slices. Methods Mol Biol 1591:9-25|
|Nath, Shubhankar; Christian, Laura; Tan, Sarah Youngsun et al. (2016) Dynein Separately Partners with NDE1 and Dynactin To Orchestrate T Cell Focused Secretion. J Immunol 197:2090-101|
|Brown, Katherine A; Yang, Xiaoping; Schipper, Desmond et al. (2015) A self-assembling lanthanide molecular nanoparticle for optical imaging. Dalton Trans 44:2667-75|
|Hu, Zicheng; Lancaster, Jessica Naomi; Ehrlich, Lauren I R (2015) The Contribution of Chemokines and Migration to the Induction of Central Tolerance in the Thymus. Front Immunol 6:398|
|Hu, Zicheng; Lancaster, Jessica N; Sasiponganan, Chayanit et al. (2015) CCR4 promotes medullary entry and thymocyte-dendritic cell interactions required for central tolerance. J Exp Med 212:1947-65|
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