Colitis in mice lacking the common cytokine receptor γ chain is mediated by IL-6-producing CD4 + T cells

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 128; no. 4; pp. 922 - 934
• Main Authors: Kai, Yasuyuki, Takahashi, Ichiro, Ishikawa, Hiromichi, Hiroi, Takachika, Mizushima, Tsunekazu, Matsuda, Chu, Kishi, Daisuke, Hamada, Hiromasa, Tamagawa, Hiroshi, Ito, Toshinori, Yoshizaki, Kazuyuki, Kishimoto, Tadamitsu, Matsuda, Hikaru, Kiyono, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2005
• Subjects: Adoptive Transfer; Animals; Antibodies, Monoclonal - pharmacology; Apoptosis; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Colitis - genetics; Colitis - metabolism; Colitis - pathology; Colon - pathology; Interleukin Receptor Common gamma Subunit; Interleukin-6 - biosynthesis; Interleukin-6 - immunology; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Mutation; Protein Isoforms - deficiency; Protein Isoforms - genetics; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Receptors, Cytokine - deficiency; Receptors, Cytokine - genetics; Receptors, Interleukin-2 - deficiency; Receptors, Interleukin-2 - genetics; Spleen - pathology; Thymus Gland - pathology; IL-6R; TCR; IL; LP; CRγ; FACS; TNF; mAb; IFN; FITC; TGF; PE; LCR; GAPDH; SP; PCR; ELISA
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2005.01.013

Background & Aims:
Mice that have a truncated mutation of the common cytokine receptor γ chain (CRγ
−/Y) are known to spontaneously develop colitis. To identify the pathologic elements responsible for triggering this localized inflammatory disease, we elucidated and characterized aberrant T cells and their enteropathogenic cytokines in CRγ
−/Y mice with colitis.
Methods:
The histologic appearance, cell population, T-cell receptor Vβ usage, and cytokine production of lamina propria lymphocytes were assessed. CRγ
−/Y mice were treated with anti-interleukin (IL)-6 receptor monoclonal antibody to evaluate its ability to control colitis, and splenic CD4
+ T cells from the same mouse model were adoptively transferred into SCID mice to see if they spurred the appearance of colitis.
Results:
We found marked thickening of the large intestine, an increase in crypt depth, and infiltration of the colonic lamina propria and submucosa with mononuclear cells in the euthymic CRγ
−/Y mice, but not in the athymic CRγ
−/Y mice, starting at the age of 8 weeks. Colonic CD4
+ T cells with high expressions of antiapoptotic Bcl-x and Bcl-2 were found to use selected subsets (Vβ14) of T-cell receptor and to exclusively produce IL-6. Treatment of CRγ
−/Y mice with anti-IL-6 receptor monoclonal antibody prevented the formation of colitis via the induction of apoptosis in IL-6-producing CD4
+ T cells. Adoptive transfer of pathologic CD4
+ T cells induced colitis in the recipient SCID mice.
Conclusions:
Colonic IL-6-producing thymus-derived CD4
+ T cells are responsible for the development of colitis in CRγ
−/Y mice.