Enhanced Formation of Azoxymethane‐induced Colorectal Adenocarcinoma in γδ T Lymphocyte‐deficient Mice

Abstract

γδ T cells have been reported to secrete a cytokine which supports the elimination of impaired epithelial cells and to maintain the normal configuration of the intestinal epithelium. 5,6) However, the precise functions of γδ T cells have not been elucidated. Some recent studies have described the effect of γδ T cells on intestinal tumor cells. γδ T cells regulated the cytotoxic activities of NK cells and CTL, of which the targets were intestinal tumor cells.7) The frequency of tumorinfiltrated γδ T cells was lowered in human well-to-moderately differentiated colorectal adenocarcinoma, 8) suggesting a relationship between γδ T cells and the formation and progression of colorectal adenocarcinoma. Notably, γδ T cells in which the variable region on the TCRδ chain is Vδ1 (Vδ1-γδ T cells) were reported to be predominant in iIEL, to recognize the major histocompatibility complex class I-related molecules A and B (MICA and MICB) and to have cytotoxic activity against intestinal tumor cells. 9)The above report also suggests that γδ T cells in iIEL may affect the formation and progression of colorectal adenocarcinoma.The present study was designed to examine the effect of γδ T cells on the formation and progression of chemically induced colorectal adenocarcinoma using γδ T cell-deficient mice. Azoxymethane (AOM) was administered to wild-type C57BL/6 mice, αβ T cell-deficient mice (TCRα-gene knockout mice) and γδ T cell-deficient mice (TCRδ-gene knockout mice) and the formation of macroscopic tumors and microscopic aberrant crypt foci in colorectal mucosa was examined. The effect of γδ T cells on the formation and progression of colorectal adenocarcinoma is discussed in the light of the results of the present study. MATERIALS AND METHODSMice Homozygous TCRα-gene knockout mice, 10) homozygous TCRδ-gene knockout mice 11) and wild-type C57BL/6 (the background of the knockout mice) were purchased from Jackson Laboratories (Bar Harbor, ME). The mice were bred and maintained in a clean air system (EBAC-S, Clea Japan Inc., Tokyo). Two-to 3-month-old mice (body weight: 15-20 g) were used for experiments. Induction of colorectal tumors and aberrant crypt foci For the induction of colorectal tumors, mice were administered AOM (10 mg/kg weight) intraperitoneally (i.p.) once

Flow cytometric assessment of autologous γδ T cells in patients with acute myeloid leukemia: Potential effector cells for immunotherapy?

“…Our findings are in line with reports of a peripheral gd T cell deficit in patients with other types of malignancies such as cutaneous primary melanoma (68) and nasopharyngeal carcinoma (70). The possibility that low levels of circulating gd T cells may contribute to the failure of immune surveillance against AML is supported by studies of gd T lymphocyte-deficient mice: These animals are highly susceptible to cutaneous carcinogenesis (72) and colorectal adenocarcinoma can be readily induced (69). Similarly, gd T lymphocyte-deficient mice targeted with pathogenic and nonpathogenic insults are susceptible to severe tissue damage and unimpeded bacterial growth (73).…”

“…We first examined gd T cell levels in AML patients at diagnosis since it has been suggested that the frequency of these cells plays a role in the balance between health and disease (3,67), and that an impairment of T cells expressing g/d TCRs may lead to a downregulation of normal immune defense (68)(69)(70). In this regard, it is of interest that in patients with advanced stage solid tumors a correlation between low gd T cell counts and short survival time has been reported (58).…”

Colon carcinogenesis in wild type and immune compromised mice after treatment with azoxymethane, and azoxymethane with dextran sodium sulfate

“…In our studies, the TCRδ −/− B6 mice showed a tumor incidence that was not statistically different from either WT or TCRβ −/− mice treated with AOM + DSS (Table ). In contrast, when TCRδ −/− B6 mice were treated with 5 weekly injections of 10 mg/kg AOM (without DSS) the tumor incidence was 50% at 7 months, while WT and TCRα −/− B6 mice did not develop CRC . B6 mice are relatively resistant to AOM as a single agent; therefore, this result in the TCRδ null animals indicates that γ/δ T‐cells may play a role in the resistance of WT B6 mice to CRC development.…”

Role of the gut as a primary lymphoid organ

“…Thus, TCR-␥␦ -deficient mice are susceptible to mutagen -induced local carcinomas [20] and to localized inflammation by toxic chemicals [21]. TCR-␣␤ + CD8␣␣ T-IEL were shown to mimic the role of CD4 + CD25 + regulatory T cells in preventing the colitis induced by injection of CD4 + naïve T cells into T cell -deficient mice; this regulation was demonstrated to be mediated by IL-10 [22].…”