New candidates for CD4 T cell pathogenicity in experimental neuroinflammation and multiple sclerosis

Abstract

Multiple sclerosis is a chronic autoimmune demyelinating disease of the central nervous system, which is thought to be triggered by environmental factors in genetically susceptible individuals leading to activation of autoreactive T lymphocytes. Large multi-centre genome-wide association studies have identified multiple genetic risk loci in multiple sclerosis. In this study, we investigated T cell transcriptomic changes in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. We correlated these findings with the multiple sclerosis risk genes postulated by the most recent Immunochip analysis and found that multiple sclerosis susceptibility genes were significantly regulated in experimental autoimmune encephalomyelitis. Our data indicate that nine distinct genes associated with multiple sclerosis risk, Bach2, Il2ra, Irf8, Mertk, Odf3b, Plek, Rgs1, Slc30a7 and Thada, can be confirmed to be differentially regulated in pathogenic CD4(+) T cells. During the effector phase within the inflamed CNS, CD4(+) T cells undergo comprehensive transformation and we identified key transcription factors and signalling networks involved in this process. The transformation was linked to metabolic changes with the involvement of liver X receptor/retinoid X receptor signalling and cholesterol biosynthesis, which might control the T cell effector function in the central nervous system. Thus, our study confirms the involvement of multiple sclerosis risk genes in the pathophysiology of the animal model and sheds light on additional disease-relevant inflammatory networks.

Loss of SFRP4 Alters Body Size, Food Intake, and Energy Expenditure in Diet-Induced Obese Male Mice

“…However, RNAseq analysis revealed no changes in the expression in Wnt ligands or their associated receptors in the hypothalamus of Sfrp4 -/-mice. While only nine genes were differentially regulated, several, including Cd4, Odf3b and Crip1, are expressed in immune cells or regulated by inflammatory stimuli (12)(13)(14). It has also been reported SFRP4 can affect endothelial cell stability, migration and proliferation in vitro (42) and another of the hypothalamic-regulated genes, Emp1, is a component of tight junctions in the blood brain barrier (15).…”

“…Surprisingly, only 4 genes were upregulated and 5 genes were downregulated in diet-induced obese Sfrp4 -/-mice (Table 1). Interestingly, several of these genes, including Cd4, Odf3b and Crip1 have roles in immune function (12)(13)(14). Emp1 is also of interest as a tight junction protein in the blood brain barrier (15).…”

The Gas6/TAM System and Multiple Sclerosis

“…In any case, a recent study assessed the transcriptomic modification that Th17 CD4 + T cells undergo, derived from mice following induction of EAE. Interestingly, MerTK is among the genes overexpressed upon EAE induction [106]. …”

Protein kinase CK2 governs the molecular decision between encephalitogenic T H 17 cell and T reg cell development

“…However, groundbreaking studies of T-cell plasticity have led to the widely accepted model that already-differentiated T cells are also able to alter their effector function in vivo. Along this line, it was demonstrated that T cells producing IFN-γ in the spinal cord during EAE originated from IL-17-producing T H 17 cells which underwent their conversion to ex-T H 17 cells by the proinflammatory cytokine IL-23 (44,45 …”