Altered Immune Responses in Interleukin 10 Transgenic Mice

T cell responses to self Ags and normal microbial flora are carefully regulated to prevent autoreactivity. Because IL-10-deficient mice develop colitis, and this response is triggered by luminal flora, we investigated whether IL-10 regulates the ability of microbial Ags to induce autoreactive T cells that could contribute to intestinal inflammation. T cells from wild-type mice were primed with staphylococcal enterotoxin B (SEB) in vitro, which induced an autoreactive proliferative response to syngeneic feeder cells. The cells were predominately CD3+ and CD4+. T cells from IL-10-deficient mice were constitutively autoreactive, and SEB priming enhanced this further. The autoreactive, proliferative response of T cells from wild-type mice was suppressed by IL-10 in the primary or secondary culture, and this effect was inhibited by neutralizing Abs to the IL-10R. To confirm that an autoreactive repertoire was expanded after SEB priming, we used CBA/J mice (Mls-1a) in which autoreactive T cells recognizing the endogenous viral superantigen are depleted (Vβ6, 7, 8.1 TCR-bearing cells). However, SEB rescued these autoreactive T cell repertoires. Adding anti-MHC class II Ab blocked the autoreactive response. SEB-primed splenic or colonic T cells also induced apoptosis in syngeneic intestinal epithelial cells that was blocked significantly by IL-10. Thus, microbial Ags have the potential to abrogate self tolerance by stimulating autoreactive T cells that become cytolytic to target cells. IL-10 plays a protective role in maintaining self tolerance after microbial stimulation by preventing the activation of T cells that contribute to epithelial cell damage.

Section: Figuresupporting

confidence: 87%

Staphylococcal Enterotoxin B Stimulates Expansion of Autoreactive T Cells That Induce Apoptosis in Intestinal Epithelial Cells: Regulation of Autoreactive Responses by IL-10

Ito

Takaishi

Jin

et al. 2000

“…Therefore, one might predict that IL-10 would also play a role in the suppression of antitumor immunity. Indeed, transgenic mice expressing IL-10 under the control of the IL-2 promoter are compromised in their ability to reject experimental lung carcinomas, while IL-10-deficient mice mount more potent Th1 and CTL responses against bladder tumors and melanomas (16,17). Furthermore, murine plasmacytomas treated with antisense IL-10 are more immunogenic than the parental cell lines (18).…”

Section: Discussionmentioning

confidence: 99%

Cutting Edge: IL-10-Producing CD4+ T Cells Mediate Tumor Rejection

Segal

Glass

Shevach

2002

IL-10 has potent immunosuppressive properties, and IL-10-producing CD4+ Tr1 cells have been characterized as regulators of Th1-mediated immunity. In this study, using a s.c. model of glioma cell growth in mice, we demonstrate that CD4+, but not CD8+, T cells play a critical role in tumor rejection following vaccination with irradiated glioma cells. Surprisingly, glioma-specific CD4+ T cells produce IL-10 but neither IL-4 nor IFN-γ, and glioma rejection is compromised in IL-10−/− hosts. Hence, our findings demonstrate that IL-10-producing CD4+ T cells can manifest antitumor functions and suggest that IL-10 may have proinflammatory effects in disease states.

“…Further studies showed that the protective effect was dependent on TGF-␤ and/or IL-10 (14,(17)(18)(19)(20), but not on IL-4 (18).…”

mentioning

confidence: 96%

Regulatory CD4 T Cells Control the Size of the Peripheral Activated/Memory CD4 T Cell Compartment

Annacker

Burlen-Defranoux

Pimenta-Araujo

et al. 2000

136

The mechanisms leading to stable T cell numbers in the periphery of a healthy animal are, to date, not well understood. We followed the expansion of CD45RBhigh (naive) and CD45RBlow (activated/memory) CD4 T cells transferred from normal mice into syngeneic Rag-20/0 recipients and the dynamics of peripheral reconstitution when both populations were coinjected. Naive cells acquired an activated phenotype and showed a high proliferative capacity that was dependent on the environment in which the recipients were kept (specific pathogen-free vs conventional housing conditions), the age of the recipients, and the presence of CD45RBlow T cells in the injected cohort. CD45RBlow CD4 T cells protected the host from CD45RBhigh CD4 T cell-induced inflammatory bowel disease and showed a limited degree of expansion. CD45RBlow CD4 T cells isolated from GF mice also showed the ability to prevent inflammatory bowel disease, indicating that at least part of the natural regulatory T cells are self-reactive. The results indicate that 1) peripheral T cell expansion in lymphocyte-deficient recipients represent classical immune responses, which are mainly promoted by exogenous Ags and 2) natural regulatory T cells control the size of the activated/memory peripheral CD4 T cell compartment.