Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral infection
- Michihiro Iwashiro*,
- Ronald J. Messer*,
- Karin E. Peterson*,
- Ingunn M. Stromnes*,
- Tomoharu Sugie†,‡, and
- Kim J. Hasenkrug*,§
- *Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; and †Stanford University Blood Center, Palo Alto, CA 94304
-
Edited by Irving L. Weissman, Stanford University School of Medicine, Stanford, CA, and approved May 23, 2001 (received for review April 9, 2001)
Abstract
Normal levels of CD4+ regulatory T cells are critical for the maintenance of immunological homeostasis and the prevention of autoimmune diseases. However, we now show that the expansion of CD4+ regulatory T cells in response to a chronic viral infection can lead to immunosuppression. Mice persistently infected with Friend retrovirus develop approximately twice the normal percentage of splenic CD4+ regulatory T cells and lose their ability to reject certain tumor transplants. The role of CD4+ regulatory T cells was demonstrated by the transmission of immunosuppression to uninfected mice by adoptive transfers of CD4+ T cells. CD4+ T cells from chronically infected mice were also immunosuppressive in vitro, inhibiting the generation of cytolytic T lymphocytes in mixed lymphocyte cultures. Inhibition occurred at the level of blast-cell formation through a mechanism or mechanisms involving transforming growth factor-β and the cell surface molecule CTLA-4 (CD152). These results suggest a possible explanation for HIV- and human T cell leukemia virus-I-induced immunosuppression in the absence of T cell depletion.
Footnotes
-
↵ ‡ Present address: First Department of Surgery, Kyoto University Medical School, Sakyo-ku, Kyoto 606-8507, Japan.
-
↵ § To whom correspondence and reprint requests should be addressed at: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South 4th Street, Hamilton, MT 59840. E-mail: khasenkrug{at}niaid.nih.gov.
-
This paper was submitted directly (Track II) to the PNAS office.
- Abbreviations:
- FV,
- Friend virus;
- CTL,
- cytotoxic T lymphocyte;
- MLC,
- mixed lymphocyte culture;
- TGF-β,
- transforming growth factor-β
- Copyright © 2001, The National Academy of Sciences
