The online version of this article (doi:10.1186/1471-2172-15-6) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
JC, DB and MTC designed the research; JC and DB conducted the research; JC, DB and MTC analyzed the research; JC and MTC wrote the manuscript. MTC had primary responsibility for final content. All authors read and approved the final manuscript.
Vitamin D receptor (VDR) deficiency contributes to the development of experimental inflammatory bowel disease (IBD) in several different models. T cells have been shown to express the VDR, and T cells are targets of vitamin D. In this article we determined the effects of VDR expression on CD8+ T cells.
VDR KO CD8+ T cells, but not WT CD8+ T cells, induced colitis in Rag KO recipients. In addition, co-transfer of VDR KO CD8+ T cells with naïve CD4+ T cells accelerated colitis development. The more severe colitis was associated with rapidly proliferating naïve VDR KO CD8+ T cells and increased IFN-γ and IL-17 in the gut. VDR KO CD8+ T cells proliferated in vitro without antigen stimulation and did not downregulate CD62L and upregulate CD44 markers following proliferation that normally occurred in WT CD8+ T cells. The increased proliferation of VDR KO CD8+ cells was due in part to the higher production and response of the VDR KO cells to IL-2.
Our data indicate that expression of the VDR is required to prevent replication of quiescent CD8+ T cells. The inability to signal through the VDR resulted in the generation of pathogenic CD8+ T cells from rapidly proliferating cells that contributed to the development of IBD.
Additional file 1: Figure S1: (A) CD8+ and CD4+column purification was followed by cell sorting. Histograms show the frequencies of CD8+ T cell subsets before (pre-sort) and after (post-sort) sorting of splenocytes from WT and VDR KO mice. (B) CD4+CD45RBhigh pre-sort and post-sort populations. The purity of the CD8+ and the CD4+CD45RBhigh T cells was >99%. (C) Dot plots show the single staining for PE-conjugated CD45.1, FITC-conjugated CD8β, and isotype controls for both PE and FITC staining in the IEL for Figure 3A. (D) Lymphocytes were first gated on TCRβ+ cells. Bar graphs shows the frequency of CD25+ T cells within the CD8+ population. Values are the mean ± SEM of 8-10 mice per group. Student’s t-tests, n.s., not significant. (PDF 299 KB)
Additional file 2: Figure S2: (A) Forward and side scatter of splenic lymphocytes. CD8β+ cells were gated on and stained for CD28, CD122 and isotype controls. (B) Forward and side scatter for the IEL and MLN. (C) Sorted CD8 cells were cultured without stimulation or with CD3/CD28 for 3 days and stained for CD8β, CD44 and CD62L antibodies. CFSE staining was analyzed in the CD44low/CD62Lhigh (naive) and CD44high/CD62Llow (activated) populations. (PDF 299 KB)
Additional file 3: Figure S3: mRNA expression for Ifn-γ, Il-17A, and Il-10 in the (A) small intestine and (B) colon of Rag KO recipients of CD4+WTCD8 or CD4+KOCD8 (same mice as Figure 2). Data is from n=6-8 mice per group. ANOVA, *P <0.05. (PDF 190 KB)
Webb AR, Pilbeam C, Hanafin N, Holick MF: An evaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25-hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr. 1990, 51 (6): 1075-1081. PubMed
Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF, de Waal-Malefyt R, Coffman RL, Hawrylowicz CM, O’Garra A: In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med. 2002, 195 (5): 603-616. 10.1084/jem.20011629. PubMedPubMedCentralCrossRef
Filaci G, Fravega M, Negrini S, Procopio F, Fenoglio D, Rizzi M, Brenci S, Contini P, Olive D, Ghio M: Nonantigen specific CD8(+) T suppressor lymphocytes originate from CD8(+)CD28(-) T cells and inhibit both T-cell proliferation and CTL function. Hum Immunol. 2004, 65 (2): 142-156. 10.1016/j.humimm.2003.12.001. PubMedCrossRef
Das G, Augustine MM, Das J, Bottomly K, Ray P, Ray A: An important regulatory role for CD4 + CD8 alpha alpha T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease. Proc Natl Acad Sci USA. 2003, 100 (9): 5324-5329. 10.1073/pnas.0831037100. PubMedPubMedCentralCrossRef
Rigby WF, Noelle RJ, Krause K, Fanger MW: The effects of 1,25-dihydroxyvitamin D3 on human T lymphocyte activation and proliferation: a cell cycle analysis. J Immunol. 1985, 135 (4): 2279-2286. PubMed
- Vitamin D receptor expression controls proliferation of naïve CD8+ T cells and development of CD8 mediated gastrointestinal inflammation
Margherita T Cantorna
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II