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Abstract
Pro-inflammatory CD4+ T helper (Th) cells drive the pathogenesis of many autoimmune conditions. Recent advances have modified views of the phenotype of pro-inflammatory Th cells in autoimmunity, extending the breadth of known Th cell subsets that operate as drivers of these responses. Heterogeneity and plasticity within Th1 and Th17 cells, and the discovery of subsets of Th cells dedicated to production of other pro-inflammatory cytokines such as GM-CSF have led to these advances. Here, we review recent progress in this area and focus specifically upon evidence for chemokine receptors that drive recruitment of these various pro-inflammatory Th cell subsets to sites of autoimmune inflammation in the CNS. We discuss expression of specific chemokine receptors by subsets of pro-inflammatory Th cells and highlight which receptors may be tractable targets of therapeutic interventions to limit pathogenic Th cell recruitment in autoimmunity.
Highlights
T helper (Th) cells play pivotal roles in tissue inflammation in a variety of human autoimmune conditions such as multiple sclerosis (MS), psoriasis and rheumatoid arthritis (RA)
Intracellular microbes are combated by the actions of IFNgsecreting Th1 cells; responses suited for expulsion of helminths and nematodes are triggered following activation of interleukin (IL)-4/5/13-secreting Th2 cells; and extracellular bacteria and fungus are controlled by phagocyte responses amplified by IL-17A/F-secreting Th17 cells
CCR5, together with CXCR3, appear to contribute to adhesion to leptomeningeal structures and influence migration of T cells from the cerebral spinal fluid (CSF) into the central nervous system (CNS) [185].Together, the evidence strongly suggests that CCR5 has a role in mediating the migration of autoinflammatory cells into the CNS during EAE, but whether CCR5 plays a prominent role in migration of recently identified inflammatory GM-CSFsecreting Th subsets will require further studies and use of experimental systems that can reveal the cell-intrinsic role of this receptor in pathogenic Th17 cells
Summary
Th cells play pivotal roles in tissue inflammation in a variety of human autoimmune conditions such as multiple sclerosis (MS), psoriasis and rheumatoid arthritis (RA). It is possible that cytokines released by early infiltrating Th17 cells (such as TNFa or IL-17A) disrupt BBB integrity and allow cells expressing chemokine receptors such as CCR2 or CXCR6 to enter the CNS directly from brain capillaries [107, 108].
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