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Regulation of alpha-v-beta-8 integrin expression and its role in intestinal immune homeostasis

Final Report Summary - ITGB8 REGULATION (Regulation of alpha-v-beta-8 integrin expression and its role in intestinal immune homeostasis)

Transforming growth factor-beta (TGF-b) plays a critical role in maintaining gut immune homeostasis. Although ubiquitously expressed, TGF-b must be activated in order to enable subsequent signaling. TGF-b activation thus represents a major point of regulation of intestinal immune responses.
I have shown that expression of alpha-v-beta-8 integrin (avb8) by dendritic cells (DCs) is required to activate TGF-b so that it can signal to T cells. Furthermore, I have shown that avb8 expression is restricted to intestinal CD103+ DCs. However the mechanisms by which avb8 expression, and thus the ability to activate TGF-b, is restricted to this subset of DCs are unknown.
In this fellowship, I propose (1) to define the mechanisms by which avb8 expression is regulated in DCs, and (2) to determine whether avb8 expression program can be manipulated in order to control intestinal inflammation.
During the two years of this project, significant progress has been made and most of objectives set for Aim 1 have been met. Two manuscripts describing results obtained in this part are currently under revision. In addition, significant advances have been made on tasks of Aim 2.
Specifically, we have been able to show that CD103+ DCs acquired b8 expression in the intestine. In addition, we have shown that b8 expression in controlled by a combination of factors that include DC lineage, and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that factors associated with the intestinal microenvironment drive expression of b8 in DCs. However, these signals only result in high levels of b8 expression in cells of the cDC1 lineage, namely the CD8a+ or CD103+CD11b- DCs, which is associated with epigenetic changes in the Itgb8 locus. Together, these data provide a key illustrative example of how microenvironmental factors and cell lineage drive the generation of regulatory avb8-expressing DCs specialized for activation of TGF-b to facilitate Treg generation. In addition, preliminary results suggest that both in mice and humans b8 expression profile in DCs is indeed altered in the context of intestinal inflammation. Two manuscripts presenting these results are currently under revision for publication at peer-reviewed scientific international journals.
Thus these studies provide a detailed understanding of how DCs acquire a key immune-regulatory function, the activation of TGF-b. Furthermore, they have been exploring whether this is disrupted in patients with Inflammatory Bowel Diseases (IBD) and if avb8 expression can be manipulated in DCs. Together, this provide new information on how intestinal homeostasis is established, and open new areas of research for the development of IBD treatment.
The increase in IBD and the chronic and debilitating nature of these disorders emphasize the relevance of a better understanding of the processes that underlie normal regulation of mucosal immune responses. The implementation of this proposal has built on both the expertise of the Host Institution and the transfer of unique know how and tools by the Applicant from Harvard Medical School. This transfer has been including both reagents and collaborations. Thus this proposal has developed long-lasting cooperation between leading US-Research center and contributed to increasing European excellence and competitiveness.