Biology of Blood and Marrow Transplantation | 2019
Spatial Compartmentalisation of T Regulatory Cells within Intestinal Lymphoid Tissue
Abstract
Gastrointestinal GVHD is the leading cause of GVHD-associated mortality. Regulatory T cells (Tregs) can suppress GVHD [Edinger 2003], whilst a disrupted gut microbiota negatively impacts transplant outcomes [Taur 2014]. Regulatory T cells (Tregs) help to control gut inflammation, but how their positioning within tissues relates to their function is unclear. Gut solitary isolated lymphoid tissues (SILTs) are organised lymphoid aggregates containing Tregs and other immune cells. We aim to understand how the location, interaction and travel of Tregs within SILTs change from steady state to inflammation. We hypothesise that the induction of microbe-specific Tregs within SILTs and their subsequent egress into the surrounding tissue play a critical role in controlling inflammation at barrier surfaces. The Powrie group has expertise in quantitative gut tissue image analysis of complex cell populations. We characterised the location and immune cell composition of caecal and colonic SILTs using confocal imaging of CD4, B220 and Foxp3 markers in specific pathogen free (SPF) and germ-free (GF) C56BL/6J mice. In SPF mice, we observe structurally mature SILTs located in the distal colon, whilst less developed SILTs reside in the caecum and proximal colon. Flow cytometric analysis show differential expression of Treg numbers and subsets within these discrete gut regions. Mature SILTs are well organised, with a central B cell zone, and an outer T cell area containing Tregs. Interestingly, we observe increased numbers of SILTs in GF compared to SPF conditions, with a greater proportion of Tregs within SILTs. Tregs within SILTs are poised to respond to inflammation, and their positioning may play key roles in damage control. Using TCR transgenic mice and in-vivo live imaging, we are currently exploring antigen-specific Treg responses in microbiome-replete and germ-free settings. Understanding the functional role of SILTs in intestinal homeostasis could identify targets for novel therapies in intestinal GVHD.