Abstract
It is now clear that functional CD4+CD25+ regulatory T (TR) cells exist as part of the normal immune population and prevent the development of intestinal inflammation. We have recently shown that CD4+CD25+ TR cells reside in the intestine and control intestinal homeostasis in humans and mice. In this study, we demonstrate that the TNF family molecule RANKL and its receptor RANK are critically involved in controlling the function of CD4+CD25+ T R cells in the intestine. We first found that RANKL was preferentially expressed on both CD4+CD25+ TR cells and colitogenic CD4+ T cells, whereas RANK was expressed on dendritic cells. Although neutralizing anti-RANKL mAb did not affect T R activity of CD4+CD25+ TR cells to suppress the proliferation of CD4+ responder cells in vitro, in vivo administration of anti-RANKL mAb abrogated CD4+CD25+ TR cell-mediated suppression of colitis induced by adoptive transfer of CD4+CD45RBhigh T cells into SCID mice. Interestingly, an adoptive transfer experiment using Ly5.1+CD4 +CD45RBhigh cells and Ly5.2+CD4 +CD25+ TR cells revealed that the ratio of CD4+CD25+ TR cells in total CD4+ T cells in inflamed mucosa was significantly decreased by anti-RANKL mAb treatment. Consistent with this, the expression of RANK on lamina propria CD11c+ cells from colitic mice was significantly increased as compared with that from normal mice, and in vitro treatment with anti-RANKL mAb suppressed the expansion of CD4+Foxp3+ TR cells in culture with colitic lamina propria CD11c+ cells. Together, these results suggest that the RANK-RANKL signaling pathway is critically involved in regulating the function of CD4+CD25+ TR cells in colitis.
| Original language | English |
|---|---|
| Pages (from-to) | 6079-6087 |
| Number of pages | 9 |
| Journal | Journal of Immunology |
| Volume | 182 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2009 May 15 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology
Cite this
Rank-rankl signaling pathway is critically involved in the function of CD4+CD25+ regulatory T cells in chronic colitis. / Totsuka, Teruji; Kanai, Takanori; Nemoto, Yasuhiro; Tomita, Takayuki; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Sakamoto, Naoya; Akiba, Hisaya; Okumura, Ko; Yagita, Hideo; Watanabe, Mamoru.
In: Journal of Immunology, Vol. 182, No. 10, 15.05.2009, p. 6079-6087.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Rank-rankl signaling pathway is critically involved in the function of CD4+CD25+ regulatory T cells in chronic colitis
AU - Totsuka, Teruji
AU - Kanai, Takanori
AU - Nemoto, Yasuhiro
AU - Tomita, Takayuki
AU - Okamoto, Ryuichi
AU - Tsuchiya, Kiichiro
AU - Nakamura, Tetsuya
AU - Sakamoto, Naoya
AU - Akiba, Hisaya
AU - Okumura, Ko
AU - Yagita, Hideo
AU - Watanabe, Mamoru
PY - 2009/5/15
Y1 - 2009/5/15
N2 - It is now clear that functional CD4+CD25+ regulatory T (TR) cells exist as part of the normal immune population and prevent the development of intestinal inflammation. We have recently shown that CD4+CD25+ TR cells reside in the intestine and control intestinal homeostasis in humans and mice. In this study, we demonstrate that the TNF family molecule RANKL and its receptor RANK are critically involved in controlling the function of CD4+CD25+ T R cells in the intestine. We first found that RANKL was preferentially expressed on both CD4+CD25+ TR cells and colitogenic CD4+ T cells, whereas RANK was expressed on dendritic cells. Although neutralizing anti-RANKL mAb did not affect T R activity of CD4+CD25+ TR cells to suppress the proliferation of CD4+ responder cells in vitro, in vivo administration of anti-RANKL mAb abrogated CD4+CD25+ TR cell-mediated suppression of colitis induced by adoptive transfer of CD4+CD45RBhigh T cells into SCID mice. Interestingly, an adoptive transfer experiment using Ly5.1+CD4 +CD45RBhigh cells and Ly5.2+CD4 +CD25+ TR cells revealed that the ratio of CD4+CD25+ TR cells in total CD4+ T cells in inflamed mucosa was significantly decreased by anti-RANKL mAb treatment. Consistent with this, the expression of RANK on lamina propria CD11c+ cells from colitic mice was significantly increased as compared with that from normal mice, and in vitro treatment with anti-RANKL mAb suppressed the expansion of CD4+Foxp3+ TR cells in culture with colitic lamina propria CD11c+ cells. Together, these results suggest that the RANK-RANKL signaling pathway is critically involved in regulating the function of CD4+CD25+ TR cells in colitis.
AB - It is now clear that functional CD4+CD25+ regulatory T (TR) cells exist as part of the normal immune population and prevent the development of intestinal inflammation. We have recently shown that CD4+CD25+ TR cells reside in the intestine and control intestinal homeostasis in humans and mice. In this study, we demonstrate that the TNF family molecule RANKL and its receptor RANK are critically involved in controlling the function of CD4+CD25+ T R cells in the intestine. We first found that RANKL was preferentially expressed on both CD4+CD25+ TR cells and colitogenic CD4+ T cells, whereas RANK was expressed on dendritic cells. Although neutralizing anti-RANKL mAb did not affect T R activity of CD4+CD25+ TR cells to suppress the proliferation of CD4+ responder cells in vitro, in vivo administration of anti-RANKL mAb abrogated CD4+CD25+ TR cell-mediated suppression of colitis induced by adoptive transfer of CD4+CD45RBhigh T cells into SCID mice. Interestingly, an adoptive transfer experiment using Ly5.1+CD4 +CD45RBhigh cells and Ly5.2+CD4 +CD25+ TR cells revealed that the ratio of CD4+CD25+ TR cells in total CD4+ T cells in inflamed mucosa was significantly decreased by anti-RANKL mAb treatment. Consistent with this, the expression of RANK on lamina propria CD11c+ cells from colitic mice was significantly increased as compared with that from normal mice, and in vitro treatment with anti-RANKL mAb suppressed the expansion of CD4+Foxp3+ TR cells in culture with colitic lamina propria CD11c+ cells. Together, these results suggest that the RANK-RANKL signaling pathway is critically involved in regulating the function of CD4+CD25+ TR cells in colitis.
UR - http://www.scopus.com/inward/record.url?scp=76949102820&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=76949102820&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.0711823
DO - 10.4049/jimmunol.0711823
M3 - Article
C2 - 19414759
AN - SCOPUS:76949102820
VL - 182
SP - 6079
EP - 6087
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 10
ER -