Two new studies about Th17 cells were published in journal Cell. Using single cell RNA-seq, these papers found additional molecular markers of Th17 pathogenicity. One of those new molecules was CD5L, a lipid scavenger receptor.
The authors, led by Vijay Kuchroo, found that CD5L expression segregated with non-pathogenic Th17 cells [induced in vitro with TGF-β1 and IL-6].
In addition, CD5L expression segregated with non-pathogenic Th17 cells in an in vivo brain inflammation model as well (compare CNS vs. spleen or intestine).
This observation was confirmed in CD5L-KO mice which showed exaggerated brain inflammation.
Adoptive transfer of in vitro [TGF-β1 and IL-6]-differentiated CD5L-KO Th17 cells indicated that absence of CD5L in T cells were sufficient to increase their pathogenicity in brain inflammation model.
Mechanistically, the authors showed that exaggerated brain inflammation with CD5L-KO T cells were related to increased production of IL-17 in Th17 effector stage [but not during naive T cell differentiation to Th17].
Since CD5L was previously implicated in lipid metabolism, the authors tested whether Th17-specific CD5L expression affected their cytokine profile via lipids. Indeed, this was a case. Specifically, it appeared that CD5L was antagonizing RORγt activity and its sensitivity to endogenous lipid ligands [such as oxysterols, a cholesterol metabolites].
In addition to CD5L, second paper in Cell showed Gpr65, Plzp, Toso were individually contributing to Th17 pathogenicity.
In summary, involvement of cholesterol metabolites in Th17 pathogenicity is clinically highly relevant.
David Usharauli
This observation was confirmed in CD5L-KO mice which showed exaggerated brain inflammation.
Adoptive transfer of in vitro [TGF-β1 and IL-6]-differentiated CD5L-KO Th17 cells indicated that absence of CD5L in T cells were sufficient to increase their pathogenicity in brain inflammation model.
Mechanistically, the authors showed that exaggerated brain inflammation with CD5L-KO T cells were related to increased production of IL-17 in Th17 effector stage [but not during naive T cell differentiation to Th17].
Since CD5L was previously implicated in lipid metabolism, the authors tested whether Th17-specific CD5L expression affected their cytokine profile via lipids. Indeed, this was a case. Specifically, it appeared that CD5L was antagonizing RORγt activity and its sensitivity to endogenous lipid ligands [such as oxysterols, a cholesterol metabolites].
In addition to CD5L, second paper in Cell showed Gpr65, Plzp, Toso were individually contributing to Th17 pathogenicity.
In summary, involvement of cholesterol metabolites in Th17 pathogenicity is clinically highly relevant.
David Usharauli
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