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 2021 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 comprehensive analyses of gene expression and chromatin accessibility in bulk populations and in 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 in order 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 additional patterns of chemokine receptor expression and function that are characteristic of such cells. We are using genome-wide analysis of chromatin and comprehensive analysis of the transcriptomes of both MAIT cells and CD4+ T cells in order 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 as novel surface proteins important for the extravasation of pro-inflammatory T cells. In the last year we have also continued to investigate mouse models of skin inflammation that have features of psoriasis, principally a model that uses topical application of a pharmaceutical cream, Aldara, which contains the TLR7/8 agonist, imiquimod. We and others had described that the chemokine receptor CCR6 is expressed by IL-23-dependent T cells that produce the cytokines IL-17 and IL-22. IL-22 and IL-17 are important in producing disease in the mouse psoriasis models and are thought to be important in causing tissue injury in some autoimmune diseases. We have shown previously that mice lacking CCR6 are resistant to the IL-23-induced disease and show diminished response to Aldara. We have continued work in the last year using two-photon microscopy in order to characterize the roles of chemokines and their receptors in trafficking and activation of lymphocytes and dendritic cells during imiquimod-induced inflammation in vivo. Addressing a different aspect of in vivo imaging, we have continued experiments to develop agents to characterize tumors in pre-clinical models.