TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice.
In previous studies, we have shown that murine CD4+CD25+ regulatory T cells produce high levels of TGF-beta1 in a cell surface and/or secreted form, and blockade of such TGF-beta1 by anti-TGF-beta curtails the ability of these cells to suppress CD25- T cell proliferation and B cell Ig production in in vitro suppressor assays. In further support for the role of TGF-beta1 in suppression by CD4+CD25+ T cells, we show in this study that another TGF-beta1-blocking molecule, recombinant latency-associated peptide of TGF-beta1 (rLAP), also reverses suppression by mouse CD4+CD25+ T cells as well as their human counterparts, CD4+CD25(high) T cells. In addition, we show that CD25- T cells exposed to CD4+CD25+ T cells in vitro manifest activation of Smad-2 and induction of CD103, the latter a TGF-beta-inducible surface integrin. In further studies, we show that while CD4+CD25+ T cells from TGF-beta1-deficient mice can suppress CD25- T cell proliferation in vitro, these cells do not protect recipient mice from colitis in the SCID transfer model in vivo, and, in addition, CD4+LAP+, but not CD4+LAP- T cells from normal mice protect recipient mice from colitis in this model. Together, these studies demonstrate that TGF-beta1 produced by CD4+CD25+ T cells is involved in the suppressor activity of these cells, particularly in their ability to regulate intestinal inflammation.
Nakamura
Kazuhiko
K
Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11N238, 10 Center Drive, Bethesda, MD 20892, USA.
Kitani
Atsushi
A
Fuss
Ivan
I
Pedersen
Aasta
A
Harada
Naohiko
N
Nawata
Hajime
H
Strober
Warren
W
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D010446:Peptide Fragments / Q000096:biosynthesis / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D011498:Protein Precursors / Q000096:biosynthesis / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D018836:Inflammation Mediators; D010446:Peptide Fragments; D011498:Protein Precursors; D015375:Receptors, Interleukin-2; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1