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 2023 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, particularly the pathway of Th17/type 17 cell differentiation. Type 17 cells are important for defense against a subset of microorganisms - including the bacteria that cause tuberculosis - and contribute to autoimmune disease. We have been investigating the co- and counter-regulation of the type 17 and other pathways using T cells that are freshly isolated or cultured under polarizing and non-polarizing conditions by using comprehensive analyses of gene expression, DNA methylation, chromatin accessibility and clonotypes using bulk populations and/or single cells. These studies revealed that human memory cells expressing CCR6, the chemokine receptor that we use to identify the type 17 population, form an elongated continuum of type 17 character along which cells can be driven by increasing levels of RORgt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The phenotypes and epigenomes of CCR6-expressing cells are stable across cell divisions under noninflammatory conditions. Nonetheless, activation in polarizing and nonpolarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the type 17 continuum to type 17 cell plasticity. 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 both dermal and umbilical vein endothelial cells from humans, and 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. Our data suggest that differences in the localization of ligands are major determinants of the receptors specific roles. We discovered recently that these cells can be induced, without activation through T cell receptors, to produce pathological cytokines after exposure to cytokines made by activated innate cells. This represents an innate-like activity that could contribute to early immune responses. We are continuing to use 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 and are studying candidate transcription factors that are likely to be important for the extravasation of pro-inflammatory T cells.