Abstract
Recently, traces of double-positive FoxP3+RORγt+ T cells were identified and viewed as dual programming differentiation intermediates geared toward development into T regulatory or Th17 cells. In this study, we report that FoxP3+RORγt+ intermediates arise in the NOD mouse T cell repertoire prior to inflammation and can be expanded with tolerogen without further differentiation. Furthermore, FoxP3+RORγt+ cells express both CD62L and membrane-bound TGFβ and use the former to traffic to the pancreas and the latter to suppress effector T cells both in vitro and in vivo. The cells perform these functions as FoxP3+RORγt+ intermediates, despite being able to terminally differentiate into either FoxP3+RORγt− T regulatory or FoxP3−RORγt+ Th17 cells on polarization. These previously unrecognized observations extend plasticity to both differentiation and function and indicate that the intermediates are poised to traffic to sites of inflammation and target diverse pathogenic T cells, likely without prior conditioning by effector T cells, thus broadening efficacy against autoimmunity.
Footnotes
This work was supported by National Institutes of Health Grants RO1DK65748 and R21AI68746 (to H.Z.). D.M.T. and J.A.C. were supported by Life Sciences Fellowships from the University of Missouri, Columbia. C.M.H. was supported by National Institute of General Medical Sciences training Grant GM008396.
The online version of this article contains supplemental material.
Abbreviations used in this paper:
- GAD
- glutamic acid decarboxylase
- hi
- high
- int
- intermediate
- mTGFβ
- membrane-bound active TGFβ
- RQ
- relative quantity
- TID
- type I diabetes
- Tregs
- T regulatory cells.
- Received October 13, 2009.
- Accepted January 21, 2010.
- Copyright © 2010 by The American Association of Immunologists, Inc.