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Origin and Function of Double Negative T cells in Lupus

狼疮双阴性 T 细胞的起源和功能

基本信息

批准号：
10512753
负责人：
Andre Ballesteros-Tato
金额：
$ 50.9万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-11-19 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512753
关键词：
Adoptive Transfer Apoptosis Autoantibodies Autoimmune Autoimmune Diseases B-Lymphocytes CD3 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Child Data Development Disease Dose Equilibrium Frequencies Generations Genetic Diseases Genetic Transcription Goals Helper-Inducer T-Lymphocyte Heterogeneity Homeostasis Human Hybrids IL17 gene Immunosuppression Immunotherapy Interleukin-2 Lupus Mediating Molecular Mus Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phenotype Plasma Cells Plasma Enhancement Play Population Production Role STAT3 gene Severity of illness Signal Transduction Systemic Lupus Erythematosus T cell response T-Cell Development T-Lymphocyte Testing Therapeutic Therapeutic Intervention autoimmune lymphoproliferative syndrome autoreactivity cytokine design experimental study in vivo inhibitor lupus prone mice novel novel therapeutic intervention prevent programs response self help single-cell RNA sequencing synergism

项目摘要

SUMMARY. Loss of B cell tolerance and production of auto-antibodies (Ab) by plasma cells (PCs) play a major role in Systemic Lupus Erythematosus (SLE) pathology. Though Ab-dependent pathogenesis can be partially controlled with immunosuppression, there is no cure for Ab-mediated disorders. One of the main limitations when developing therapeutic strategies aimed to prevent Ab-dependent pathology is the lack of a precise understanding of how auto-reactive PCs are generated and maintained. In this regard, T follicular helper (Tfh) cells, a subset of CD4+ T cells that provides help to B cells, play a critical role in promoting auto-reactive PCs. As such, the expansion of self-reactive Tfh cells correlates with auto-Ab production and disease severity in murine and human lupus. Similar to Tfh cells, Double-negative (DN) T cells, a particular population of T cells that characteristically lack CD4 and CD8 expression, are also expanded in lupus. Importantly, the frequency of DN T cells also correlates with disease activity and auto-Ab production. Thus, it is generally believed that these cells play a role in autoimmune disease pathogenesis. Despite their putative role in disease development, we do not know what signals control DN T cell formation, and their exact origin and pathogenic function remain largely elusive. Furthermore, the mechanisms that regulate DN T cell homeostasis are entirely unknown, and there are currently no therapies to selectively deplete DN T cells in vivo. The main goal of this proposal is to define the cellular and molecular mechanisms that control pathogenic DN T cell development and function. In this regard, our preliminary data demonstrate that DN T cells and Tfh cells share phenotypic, transcriptional, and developmental requirements. As such, we have identified a population of Bcl6+ DN T cells that phenotypically resemble Tfh cells. The central hypothesis that will be tested in this proposal is that Tfh cells are the precursors of Bcl6+ DN T cells and that, similar to Tfh cells, these cells are efficient B cell helpers. Importantly, our preliminary data also suggest that Bcl6+ DN T cells are more plastic than Tfh cells, which allows them to acquire a “hybrid” Tfh/Th17 signature that we believe is critical for supporting auto-reactive PC responses. In Aim 1, we will test the hypothesis that Tfh cells are precursors of Bcl6+ DN T cells and examine the capacity of these cells to help self-reactive B cell responses. In Aim 2.1, we will test the hypothesis that IL- 17 production by DN T cells is critical for supporting PC responses and Ab-mediated pathology. In Aim 2.2, we will determine the molecular mechanisms controlling the acquisition of a “hybrid” Tfh/Th17 signature. Finally, in Aim 3, we will develop a new synergistic IL-2-based immunotherapy aimed to selectively target Tfh and prevent the differentiation of IL-17+Bcl6+DN T cells by combining “ultra-low” doses of rIL-2 with STAT3- signaling blockade. We believe that our studies will provide a new paradigm for how pathogenic DN T cells are generated, will reveal new pathways implicated in autoimmune disease pathogenesis, and will be crucial for designing new therapeutic interventions to target Tfh and DN T cells and prevent Ab-mediated pathology.

总结。B细胞耐受性的丧失和浆细胞自身抗体（Ab）的产生是主要原因