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Open Access Research

CD4+CD25+ T regulatory cells activated during feline immunodeficiency virus infection convert T helper cells into functional suppressors through a membrane-bound TGFβ / GARP-mediated mechanism

Michelle M Miller12, Christopher S Petty3, Mary B Tompkins12 and Jonathan E Fogle124*

  • * Corresponding author: Jonathan E Fogle jefogle@ncsu.edu

  • † Equal contributors

Author Affiliations

1 Immunology Program, North Carolina State University, Raleigh NC, USA

2 Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine, Raleigh NC 27607, USA

3 Current address: Immunotherapy Technologies, LLC, 621 Hutton Street, Suite 105, Raleigh NC 27606, USA

4 College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA

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Virology Journal 2014, 11:7  doi:10.1186/1743-422X-11-7

Published: 18 January 2014

Abstract

Background

We and others have previously reported that cell membrane-bound TGFβ (mTGFβ) on activated T regulatory (Treg) cells mediates suppressor function. Current findings suggest that a novel protein known as Glycoprotein A Repetitions Predominant (GARP) anchors mTGFβ to the Treg cell surface and facilitates suppressor activity. Recently, we have described that GARP+TGFβ+ Treg cells expand during the course of FIV infection. Because Treg cells are anergic and generally exhibit poor proliferative ability, we asked how Treg homeostasis is maintained during the course of feline immunodeficiency virus (FIV) infection.

Results

Here, we report that Treg cells from FIV+ cats express GARP and mTGFβ and convert T helper (Th) cells into phenotypic and functional Treg cells. Th to Treg conversion was abrogated by anti-TGFβ or anti-GARP treatment of Treg cells or by anti-TGFβRII treatment of Th cells, suggesting that Treg cell recruitment from the Th pool is mediated by TGFβ/TGFβRII signaling and that cell-surface GARP plays a major role in this process.

Conclusions

These findings suggest Th to Treg conversion may initiate a cascade of events that contributes to the maintenance of virus reservoirs, progressive Th cell immunosuppression, and the development of immunodeficiency, all of which are central to the pathogenesis of AIDS lentivirus infections.

Keywords:
FIV; HIV; AIDS; Lentivirus; Treg cells; mTGFβ; GARP