The Lupus Susceptibility Gene Pbx1 Regulates the Balance between Follicular Helper T Cell and Regulatory T Cell Differentiation.
Pbx1 controls chromatin accessibility to a large number of genes and is entirely conserved between mice and humans. The Pbx1-d dominant-negative isoform is more frequent in CD4(+) T cells from lupus patients than from healthy controls. Pbx1-d is associated with the production of autoreactive T cells in mice carrying the Sle1a1 lupus-susceptibility locus. Transgenic (Tg) expression of Pbx1-d in CD4(+) T cells reproduced the phenotypes of Sle1a1 mice, with increased inflammatory functions of CD4(+) T cells and impaired Foxp3(+) regulatory T cell (Treg) homeostasis. Pbx1-d-Tg expression also expanded the number of follicular helper T cells (TFHs) in a cell-intrinsic and Ag-specific manner, which was enhanced in recall responses and resulted in Th1-biased Abs. Moreover, Pbx1-d-Tg CD4(+) T cells upregulated the expression of miR-10a, miR-21, and miR-155, which were implicated in Treg and follicular helper T cell homeostasis. Our results suggest that Pbx1-d impacts lupus development by regulating effector T cell differentiation and promoting TFHs at the expense of Tregs. In addition, our results identify Pbx1 as a novel regulator of CD4(+) T cell effector function.
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610.
Seung-Chul
0000-0001-6230-9087
SC
Choi
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610.
Tarun E
0000-0002-9175-7222
TE
Hutchinson
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610.
Anton A
0000-0003-2751-2340
AA
Titov
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610.
Howard R
0000-0001-7002-0187
HR
Seay
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610.
Shiwu
S
Li
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610.
Todd M
0000-0003-2878-9296
TM
Brusko
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610.
Byron P
BP
Croker
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610.
Shahram
0000-0002-2336-8452
S
Salek-Ardakani
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610 morel@ufl.edu.
Laurence
L
Morel
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000276:immunology*; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C083400:PBX1 protein, human