Exacerbating role of gammadelta T cells in chronic colitis of T-cell receptor alpha mutant mice.
OBJECTIVE
T-cell receptor (TCR) gammadelta T cells are an important component of the mucosal immune system and regulate intestinal epithelial homeostasis. Interestingly, there is a significant increase in gammadelta T cells in the inflamed mucosa of patients with ulcerative colitis (UC). However, the role of gammadelta T cells in chronic colitis has not been fully identified.


METHODS
TCRalpha-deficient mice, which spontaneously develop chronic colitis with many features of human UC including an increase in gammadelta T-cell population, represent an excellent model to investigate the role of gammadelta T cells in UC-like colitis. To identify the role of gammadelta T cells in this colitis, we herein have generated TCRgamma-deficient mice through deletion of all TCR Cgamma genes (Cgamma1, Cgamma2, Cgamma3, and Cgamma4) using the Cre/loxP site-specific recombination system and subsequently crossing these mice with TCRalpha-deficient mice.


RESULTS
An increase in colonic gammadelta T cells was associated with the development of human UC as well as UC-like disease seen in TCRalpha-deficient mice. Interestingly, the newly established TCRalpha(-/-) x TCRgamma(-/-) double mutant mice developed significantly less severe colitis as compared with TCRalpha-deficient mice. The suppression of colitis in TCRalpha(-/-) x TCRgamma(-/-) double mutant mice was associated with a significant reduction of proinflammatory cytokine and chemokine productions and a decrease in neutrophil infiltration.


CONCLUSIONS
gammadelta T cells are involved in the exacerbation of UC-like chronic disease. Therefore, gammadelta T cells may represent a promising therapeutic target for the treatment of human UC.
Nanno
Masanobu
M
Yakult Central Institute for Microbiological Research, Tokyo, Japan.
Kanari
Yasuyoshi
Y
Naito
Tomoaki
T
Inoue
Nagamu
N
Hisamatsu
Tadakazu
T
Chinen
Hiroshi
H
Sugimoto
Ken
K
Shimomura
Yasuyo
Y
Yamagishi
Hideo
H
Shiohara
Tetsuo
T
Ueha
Satoshi
S
Matsushima
Kouji
K
Suematsu
Makoto
M
Mizoguchi
Atsushi
A
Hibi
Toshifumi
T
Bhan
Atul K
AK
Ishikawa
Hiromichi
H
D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D009504:Neutrophils / Q000473:pathology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology
D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta