Activities Of Chemokines In Health and Disease

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

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, and to understand the contributions of the chemokine system to infectious and inflammatory/autoimmune disease and cancer. Chemokines and their receptors are critical for leukocyte trafficking, and our experiments are directed to understanding how blocking or otherwise manipulating the chemokine system could be used in treating disease. In FY 2022 we have continued to study the differentiation pathways of human memory CD4+ T cells by analyzing bona fide subsets of T cells from healthy donors ex vivo. We have used chemokine receptors to identify cells along the differing pathways of memory/effector Th cell differentiation and have been investigating the co- and counter regulation of these pathways using culturing under polarizing and non-polarizing conditions, and comprehensive analyses of gene expression, DNA methylation, chromatin accessibility and clonotypes using bulk populations and/or single cells. We have continued studies of the process whereby effector/memory T cells migrate from the blood, across the layer of endothelial cells that line the inside of the blood vessel, into a site of tissue infection or inflammation. We have built on our work with mucosal-associated invariant T (MAIT) cells to investigate the mechanisms underlying the ability of human CD4+ T cells that co-express multiple chemokine receptors to extravasate efficiently, and how extravasation and T cell effector function may be coordinately regulated at the level of gene regulation. We have expanded our studies to use endothelial cells activated by different pro-inflammatory cytokines. We have focused recently on specific and redundant activities of chemokine receptors on CD4+ T cells with a pathological phenotype and have identified patterns of chemokine receptor expression and function that are characteristic of such cells. In some cases, activities of receptors are determined by differences in the localization of ligands. We are using genome-wide analysis of chromatin and comprehensive analysis of the transcriptomes of both MAIT cells and CD4+ T cells to identify shared mechanisms of gene regulation that underlie the ability of the cells to migrate efficiently. From these analyses we have identified candidate transcription factors important for the extravasation of pro-inflammatory T cells. We have also been investigating novel candidate effector proteins that may contribute to efficient T cell extravasation. In the last year we have also continued to investigate mouse models of skin inflammation that have features of psoriasis. We have contributed to work using an IL-23-dependant model of psoriasis-like inflammation in which it was demonstrated that secondary bile acids reduce skin pathology through mechanisms that include decreasing the number of IL-17A-producing T cells and inhibiting the production of the CCR6 ligand, CCL20, by keratinocytes. These effects may be mediated by the decrease in expression and activity of RORgammat, the master regulator of the Th17 program. We demonstrated that the effects of these bile acids extended beyond mice to inhibiting IL-17A production by human T cells, raising the possibility that bile acids or molecular mimics could be used for therapy as anti-inflammatory agents.