TGF-beta1 production by CD4+ CD25+ regulatory T cells is not essential for suppression of intestinal inflammation.
Naturally occurring CD4+ CD25+ regulatory T cells (Treg) are potent suppressors of CD4+ and CD8+ T cell responses in vitro and inhibit several organ-specific autoimmune diseases. While most in vitro studies suggest that CD4+ CD25+ Treg cells adopt a cytokine-independent but cell contact-dependent mode of T cell regulation, their precise mechanism of suppression in vivo remains largely unknown. Here we examine the functional contribution of Treg cell-derived TGF-beta1 and effector T cell responsiveness to TGF-beta in CD4+ CD25+ T cell-mediated suppression of inflammatory bowel disease (IBD). We show that CD4+ CD25+ Treg cells from either TGF-beta1+/+ or neonatal TGF-beta1-/- mice can suppress the incidence and severity of IBD as well as colonic IFN-gamma mRNA expression induced by WT CD4+ CD25- effector T cells. Furthermore, TGF-beta-resistant Smad3-/- CD4+ CD25+ Treg cells are equivalent to WT Treg cells in their capacity to suppress disease induced by either WT or Smad3-/- CD4+ CD25- effector T cells. Finally, anti-TGF-beta treatment exacerbates the colitogenic potential of CD4+ CD25- effector T cells in the absence of CD4+ CD25+ Treg cells. Together, these data demonstrate that in certain situations CD4+ CD25+ T cells are able to suppress intestinal inflammation by a mechanism not requiring Treg cell-derived TGF-beta1 or effector T cell/Treg cell responsiveness to TGF-beta via Smad3.
Kullberg
Marika C
MC
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Hay
Valerie
V
Cheever
Allen W
AW
Mamura
Mizuko
M
Sher
Alan
A
Letterio
John J
JJ
Shevach
Ethan M
EM
Piccirillo
Ciriaco A
CA
D019264:Adoptive Transfer; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D005434:Flow Cytometry; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*; D053773:Transforming Growth Factor beta1
D015704:CD4 Antigens; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma