Lineage-specific effects of 1,25-dihydroxyvitamin D(3) on the development of effector CD4 T cells.
Vitamin D deficiency is implicated in autoimmune disease. We therefore evaluated the effects of 1α,25-dihydroxyvitamin D(3) (1,25-D(3)), the active form of vitamin D, on the development of T helper 1 (Th1), Th17, and Th9 cells, which are implicated in the pathogenesis of different types of autoimmunity. 1,25-D(3) compromised the development of Th17 and Th9 cells, including IL-22-expressing cells while simultaneously increasing the frequency of IL-10-competent cells. Relative to Th17 and Th9 cells, the effects of 1,25-D(3) on Th1 cells were modest, reflecting the significantly reduced levels of the receptor for vitamin D in this lineage. The use of cells deficient in IL-10 or antibodies that block IL-10 signaling abolished the inhibitory effect of 1,25-D(3) on Th9 cells but had no effect on inhibition of Th17 cell frequencies. Thus, the induction of IL-10 in cultures of Th9 cells is an important mechanism by which 1,25-D(3) compromises Th9 development but does not explain inhibition of Th17 cells. A survey of select representatives of the Th17 transcriptome revealed that the levels of mRNA that encode RORγt, IL-17A, IL-17F, IL-23R, and IL-22, were reduced by 1,25-D(3), whereas IL-21 and aryl hydrocarbon receptor mRNA remained unchanged. These data suggest that vitamin D deficiency may promote autoimmunity by favoring the inordinate production of Th17 and Th9 cells at the expense of regulatory IL-10-producing T cells.
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Matthew T
MT
Palmer
Yun Kyung
YK
Lee
Craig L
CL
Maynard
James R
JR
Oliver
Daniel D
DD
Bikle
Anton M
AM
Jetten
Casey T
CT
Weaver
D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D002117:Calcitriol / Q000494:pharmacology*; D019070:Cell Lineage / Q000187:drug effects* / Q000276:immunology; D020869:Gene Expression Profiling; D016753:Interleukin-10 / Q000378:metabolism; D016906:Interleukin-9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018417:Th1 Cells / Q000166:cytology*; D058504:Th17 Cells / Q000166:cytology*; D014815:Vitamins / Q000494:pharmacology*
D016906:Interleukin-9; D014815:Vitamins; D016753:Interleukin-10; D002117:Calcitriol