Activities Of Chemokines In Health and Disease

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

The purposes of the project are to investigate the biological roles of members of the chemokine family of cytokines, to use chemokine receptors to understand the relationships between the trafficking patterns and broader biological functions of subsets of effector/memory T cells, to understand how the program for T cell extravasation is regulated, to understand the contributions of the chemokine system to infectious and inflammatory/autoimmune disease, and to use chemokines as markers to follow immune responses in vivo. Chemokines and their receptors are critical for leukocyte trafficking, and our experiments are directed at understanding how blocking or otherwise manipulating the chemokine system could be used in treating disease. In FY 2025 we have continued using chromatin accessibility using bulk populations and/or single cells, DNA methylation and new methods for analyzing genome-wide binding of transcription factors to study the roles for the gene regulatory network that underlies circadian rhythms in the differentiation and maintenance of the type 17 phenotype in human Th cells. We have found that components of the circadian network have roles specifically in the activities of human type 17 Th cells. We have studied human Th cells that co-express the chemokine receptors CCR6 and CCR2 and shown that these cells have features of cells that are pathogenic in mouse models of autoimmune diseases. We found that these cells are particularly efficient at migrating across cytokine-activated endothelial cells and would be expected to be the earliest Th cells migrating from blood into inflamed/infected tissue sites. Importantly, we identified separate roles for CCR6 and CCR2 and other chemokine receptors in the separate steps needed for the migration of these T cells from the blood across the cells that line the blood vessel lumens. In FY 2025 we have continued studies of transcription factors regulating the extravasation of human T cells, including the highly differentiated Th cells and mucosal-associated invariant T (MAIT) cells. Comprehensive investigations of the activities of these transcription factors using gene knockdown and overexpression and genome-wide analyses of transcription factor binding sites should identify gene regulatory networks that mediate the complex migratory behavior of early-responding, pro-inflammatory human T cells. In FY 2025, we have continued studies of mouse models of psoriasis-like skin inflammation using novel mouse strains and intravital microscopy to understand in detail the mechanisms for the associated T cell migration in the dermis and epidermis. We have found that the early stages of migration are mediated both by CCR6 and other receptors and we are studying how migration contributes to T cells activation that drives the immunopathology.