Abstract
Our previous studies have shown that Peyer's patches (PPs) play a key role in the induction of oral tolerance. Therefore, we hypothesized that PPs are an important site for Transforming Growth Factor (TGF)- β signaling and sought to prove that this tissue is of importance in oral tolerance induction. We found that expression of TGF-β type II receptor (TGFβRII) by CD4+ T cells increases and persists in the PPs of normal C57BL/6 mice after either high- or low-dose feeding of OVA when compared to mesenteric lymph nodes (MLNs) and spleen. Approximately one-third of these TGFβRII+ CD4+ T cells express the transcription factor Foxp3. Interestingly, the number of TGFβRII+ CD4+ T cells in PPs decreased when OVA-fed mice were orally challenged with OVA plus native cholera toxin (CT). In contrast, numbers of TGFβRII+ CD4+ T cells were increased in the intestinal lamina propria (iLP) of these challenged mice. Further, these PP CD4+ TGFβRII+ T cells upregulated Foxp3 within 2 hours after OVA plus CT challenge. Mice fed PBS and challenged with OVA plus CT did not reveal any changes in TGFβRII expression by CD4+ T cells. In order to test the functional property of TGFβRII in the induction of oral tolerance, CD4dnTGFβRII transgenic mice, in which TGFβRII signaling is abrogated from all CD4+ T cells, were employed. Importantly, these mice could not develop oral tolerance to OVA. Our studies show a critical, dose-independent, role for TGFβRII expression and function by CD4+ T cells in the gut-associated lymphoid tissues, further underlining the vital role of PPs in oral tolerance.
Highlights
Oral tolerance is a function of the mucosal immune system by which the host is protected from deleterious immune responses to innocuous gut antigens (Ags) [1,2]
In this study we showed that within 24 h of inducing oral tolerance, TGFbRII expression by CD4+ T cells in the Peyer’s patches (PPs) is significantly upregulated
Many studies have shown that Transforming Growth Factor (TGF)-b1 plays a central role in the development of acquired-type Ag-specific T regulatory cells (Tregs), through the induction and maintenance of Foxp3 expression in CD25- and CD25+ T cells, respectively [25,26,27,46]
Summary
Oral tolerance is a function of the mucosal immune system by which the host is protected from deleterious immune responses to innocuous gut antigens (Ags) [1,2]. Large doses of Ag or prolonged exposure to small doses of Ag induce a state of mucosal and systemic unresponsiveness that is characterized by reduced Agspecific IgG and helper T cell responses in the presence of protective S-IgA antibody (Ab) production [1,2,3]. When oral tolerance is disrupted, allergy and inflammatory bowel diseases can occur. It has been proposed that harnessing oral tolerance can be an effective means of treating various diseases, from allergy to autoimmunity [1,4,5,6,7,8,9]. Large doses of Ag are understood to induce anergy–a failure to respond to the Ag–and/or deletion of Ag-specific T cells, while small recurrent doses of Ag lead to the development of Ag-specific T regulatory cells (Tregs) which in turn suppress surrounding T cells by the production of inhibitory cytokines, such as TGF-b1 and IL-10
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
