Chemokine-Driven Migration of Pro-Inflammatory CD4+ T Cells in CNS Autoimmune Disease

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.

Endothelial Caveolin-1 and CXCL10 promote transcellular migration of autoreactive T cells across the blood-brain barrier

“…Chemokines including CXCL10 are upregulated in the cerebrovasculature in neuroinflammatory disease (Heng et al, 2022; Karin, 2020; Liebner et al, 2018; Manes et al, 2022). The spatial distribution of CXCL10 influences whether infiltrating leukocytes can cross the brain EC, are retained in perivascular spaces, or are able to enter the brain parenchyma (Giladi et al, 2020; Heng et al, 2022; Muller et al, 2010).…”

“…Chemokines including CXCL10 are upregulated in the cerebrovasculature in neuroinflammatory disease (Heng et al, 2022; Karin, 2020; Liebner et al, 2018; Manes et al, 2022). The spatial distribution of CXCL10 influences whether infiltrating leukocytes can cross the brain EC, are retained in perivascular spaces, or are able to enter the brain parenchyma (Giladi et al, 2020; Heng et al, 2022; Muller et al, 2010). Endothelial cells outside of the nervous system are known to promote transendothelial T cell migration by the regulated release of intracellular chemokine stores at locations of intimate leukocyte-endothelial interaction (Schoppmeyer et al, 2022; Shulman et al, 2011).…”

“…Anti-CD18 did not eliminate adhesion, suggesting additional and alternative interactions including selectins, VCAM, and antigen presentation also contribute to initial firm adhesion (Fig. 2B) (Heng et al, 2022;Manes et al, 2022;Mapunda et al, 2022). We went on to assess the role of LFA-1 on transcellular and paracellular diapedesis.…”

TCF-7 differentially regulates CD4 T cells mediated alloimmunity

“…This could be due to higher expression of T-bet 56 . Since chemokine receptor expression on T cells is central to several T cell-mediated diseases 93,94 , determining whether TCF-7 regulates chemokine expression either positively or negatively was critically important. We uncovered that mature splenic CD4 T cells from TCF-7 cKO mice expressed higher levels of chemokine receptors than CD4 T cells from WT mice both pre-and post-allo-HSCT.…”

Microglial expression of CD83 governs cellular activation and restrains autoimmune neuroinflammation

“…Importantly, the chemokines Ccl4 and Ccl5, which recruit pathogenic T cells [39], were also signi cantly elevated in sorted MDCs from CD83 ΔMG mice (Fig S3E). Monocyte-derived APCs are the key cells that interact with encephalitogenic T cells and drive neuroin ammation [11], and thus, we next investigated the T cell subsets in ltrating the CNS of EAE animals.…”