Investigation of the role of CD161+ Tregs in the pathogenesis of Crohn's disease through spatial transcriptomics.

• Grant number: 25/00112-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2025
• End date: August 31, 2028
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Raphael Sanches Peres
• Grantee: Anderson dos Santos Ramos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/17817-1 - Identification of cell interactions that affect regulatory T cells function in inflammatory bowel diseases, AP.JP

Abstract

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic disorders of the gastrointestinal tract characterized by persistent inflammation. In recent years, the incidence of IBD has increased significantly in various countries, including Brazil, where the number of diagnoses nearly tripled between 2012 and 2020. One of the main challenges in developing effective therapies lies in the still limited understanding of the cellular and molecular mechanisms involved in IBD pathophysiology. Foxp3+ regulatory T cells (Tregs) play a crucial role in maintaining immune homeostasis and controlling inflammation. Recent evidence suggests that a specific Treg subpopulation expressing CD161, a C-type lectin receptor found on certain immune cells, may be involved in tissue repair and modulation of intestinal inflammation. Indeed, CD patients who respond to anti-TNF therapy-the first-line biological treatment for IBD-show an increased frequency of intestinal CD161+ Tregs following treatment. However, the functional role of these cells in CD pathogenesis, as well as their spatial organization in intestinal tissue during both active and remission phases of the disease, remains poorly understood. This project aims to investigate the role of CD161-expressing Tregs in the pathogenesis of CD. To this end, we will perform a detailed characterization of circulating and intestinal CD161+Tregs in CD patients and murine models of colitis using multiparametric spectral flow cytometry. In addition, we will employ Visium HD spatial transcriptomics platform to map the spatial organization of these cells in intestinal tissue, as well as their interactions with other cellular populations. Functional in vitro assays, including co-cultures and 3D intestinal organoid models, will be conducted to determine cell interactions that modulate the activity and function of CD161+Tregs. These assays will also explore the direct modulation of CD161 activity using agonists or antagonists, aiming to understand its functional impact on Tregs. Finally, we will evaluate the therapeutic potential of manipulating CD161 expression or function in Tregs using experimental models of intestinal inflammation. This study is expected to significantly contribute to the understanding of Treg function in CD, particularly the CD161+Treg subset, paving the way for the development of novel therapeutic strategies based on the modulation of Treg regulatory function. (AU)