Abstract
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.
Footnotes
This work was supported by National Institutes of Health Grants R01 AI045050 (to L.M.) and R01 AI087734 (to S.S.-A.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- ANA
- anti-nuclear Ab
- B6
- C57BL/6J
- B6.Foxpegfp
- B6.Foxp3-enhanced GFP
- B6.Ly5a
- B6.SJL-PtprcaPep3b/BoyJ
- BM
- bone marrow
- B6.OT-II
- B6.Cg-Tg(TcraTcrb)425Cbn/J
- B6.Rag-1−/−
- B6.129S7-Rag1tm1Mom/J
- B6.Sle1a1
- B6.Sle1a.1NZW/NZW
- GC
- germinal center
- iTreg
- induced Treg
- miRNA
- microRNA
- mLN
- mesenteric lymph node
- pTreg
- peripheral Treg
- RA
- retinoic acid
- SLE
- systemic lupus erythematosus
- TC
- B6.NZM-Sle1NZM2410/AegSle2NZM2410/AegSle3NZM2410/Aeg/LmoJ
- TD
- T dependent
- TEff
- effector T cell
- TEM
- effector memory T cell
- TFH
- follicular helper T cell
- TFR
- follicular regulatory T cell
- Tg
- transgene/transgenic
- TN
- naive T cell
- Treg
- Foxp3+ regulatory T cell
- tTreg
- thymic Treg.
- Received October 26, 2015.
- Accepted May 11, 2016.
- Copyright © 2016 by The American Association of Immunologists, Inc.