Ann. N.Y. Acad. Sci. ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Steroids in Neuroendocrine Immunology and Therapy of Rheumatic Diseases I

The vitamin D receptor turns off chronically activated T cells Margherita T. Cantorna1,2 and Amanda Waddell1 1 2

Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, Pennsylvania. Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, Pennsylvania

Address for correspondence: Margherita T. Cantorna, M.D., Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, 115 Henning Bldg., University Park, PA 16802. [email protected]

T cell proliferation and T helper (TH ) cells that make IL-17 (TH 17 cells) and IFN-␥ (TH 1 cells) have been shown to be inhibited by 1,25(OH)2 D3 . Previous work has shown that immune-mediated diseases, where TH 1 and TH 17 cells are pathogenic, are ameliorated with 1,25(OH)2 D3 treatment. Paradoxically, infectious diseases that require TH 1 and TH 17 responses for host resistance are unaffected by 1,25(OH)2 D3 treatment. Resting T cells are not responsive to vitamin D because they do not express the vitamin D receptor (VDR) until late after activation. T cells activated following an infection help clear the infection, and since the antigen is eliminated, vitamin D is not needed to dampen the immune response. Conversely, in immune-mediated disease, there is chronic T cell activation, and in this scenario, vitamin D and 1,25(OH)2 D3 are critical for inhibiting T cell proliferation and cytokine production. Vitamin D is a late regulator of T cell function and acts to turn off T cells. This paper will review these data. Keywords: vitamin D; inflammatory bowel diseases; CD8 T cells; TH 17

Introduction Vitamin D is a fat-soluble vitamin that is critical in the regulation of calcium homeostasis and thus bone mineralization. The diet can be a source of vitamin D, although most foods in the U.S. diet are poor sources of vitamin D. For this reason, dairy products have been fortified with vitamin D. In addition to diet, exposure of the skin to sunlight releases previtamin D that is quickly converted to vitamin D. In the early 1980s, vitamin D receptors (VDRs) were identified in cells of the immune system.1,2 All cells of the immune system, including T cells, have since been shown to express the VDR.3 There must be a reason why T cells express the VDR. Therefore, current research in our lab focuses on understanding what physiologic role the VDR has in T cells. In this paper, we review our current understanding of the paradoxical effects of vitamin D on T cells. The effects of 1,25(OH)2 D3 on T cell function Early experiments that aimed at understanding the effects of vitamin D on immune function added

the active form of vitamin D, 1,25(OH)2 D3 , to peripheral blood mononuclear cells (PBMCs) from humans in vitro.4,5 PBMCs that were stimulated with T cell–specific mitogens in the presence of 1,25(OH)2 D3 proliferated less and produced less interleukin (IL)-2 and interferon (IFN)-␥ .6 Since the early studies, 1,25(OH)2 D3 has been shown to inhibit other cytokines made by T cells, including IL-17 and tumor necrosis factor-␣.7–9 T helper (TH ) cells that make IFN-␥ (TH 1 cells) and IL17 (TH 17 cells) are pathogenic in several different immune-mediated diseases (e.g., multiple sclerosis and inflammatory bowel disease (IBD)) and protective against viral and bacterial infections. Other effects of 1,25(OH)2 D3 in vitro include the induction of FoxP3-expressing IL-10–producing regulatory T (Treg ) cells, induction of the gut homing marker CCR10, and the induction of TH 2 cells.10–12 Overall, 1,25(OH)2 D3 stops T cell proliferation, inhibits TH 1 and TH 17 responses, induces Treg cells, increases gut homing of T cells, and induces IL-4 production in vitro. 1,25(OH)2 D3 also has indirect effects on T cell functions and can regulate T cells through effects on doi: 10.1111/nyas.12408

70

C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1317 (2014) 70–75 

Cantorna & Waddell

dendritic cell (DC) functions. 1,25(OH)2 D3 inhibits maturation of DCs and maintains an immature and tolerogenic phenotype by inhibiting activation markers, including major histocompatibility complex (MHC) class II, CD40, CD80, and CD86.13 Furthermore, 1,25(OH)2 D3 inhibited IL-12, enhanced IL-10 secretion, and induced apoptosis of DCs.13 Adoptive transfer of in vitro 1,25(OH)2 D3 -treated DCs prevented allograft rejection in vivo, demonstrating that 1,25(OH)2 D3 treatment of DCs can affect T cell responses in vivo.14 In addition to the direct effects of 1,25(OH)2 D3 on T cells there are indirect effects of 1,25(OH)2 D3 on T cells through the regulation of DC function. Vitamin D and inflammatory bowel disease On the basis of the effects of 1,25(OH)2 D3 in vitro on CD4+ T cell responses, we hypothesized that vitamin D would be beneficial in immune-mediated diseases, such as IBD, which is a complex family of diseases with two main subtypes, Crohn’s disease and ulcerative colitis. The causes of IBD are still not well understood, although there is a clear genetic predisposition for IBD, as the risk of developing IBD increases if one has a biological relative, especially a sibling, with IBD.15 However, monozygotic twin studies also highlight a role for the environment since the concordance rate for IBD in identical twins is only 18–50%. Environmental factor(s) that account for differential expression of disease in twins are so far poorly described.16 The bacterial microbiota are thought to play a role in the development of IBD since antibiotics ameliorated symptoms in some individuals with Crohn’s disease, and germ-free mice did not develop symptoms of experimental IBD.17,18 By determining what geographical areas have higher rather than lower rates of IBD, additional environmental factors can be identified. The incidence of IBD is higher in urban versus rural and northern versus southern parts of Europe and North America. In addition, IBD is a disease of the developed world. This geographical pattern of disease is consistent with a possible role of sunlight and vitamin D as a potential environmental factor in IBD.19 Furthermore, it has been shown that vitamin D status was low in patients with IBD, and IBD patients also had problems with bone disease.20,21 The data from humans suggest that environmental exposure to vitamin D, either from diet or sunlight, might be a factor in the etiology of IBD.

Vitamin D and T cells

There are several different animal models of IBD that have been useful for understanding the pathogenesis of IBD and identifying novel treatments. Vitamin D deficiency accelerated the development of experimental IBD in IL-10 knockout (KO) mice, and treating IL-10 KO mice with 1,25(OH)2 D3 suppressed the development of disease.22 In addition, other immune-mediated diseases (such as multiple sclerosis and diabetes), where TH 1 and TH 17 cells are pathogenic, were ameliorated with 1,25(OH)2 D3 treatment.9,23,24 Double IL-10/VDR KO mice developed a fulminating form of IBD that resulted in the premature lethality of the mice by 5 weeks of age.25 Other experimental IBD models were more severe in the VDR KO mouse (dextran sodium sulfate induced) or when VDR KO T cells were used to induce IBD (T cell transfer into immunodeficient mice).25,26 The evidence clearly shows that vitamin D and/or vitamin D deficiency exacerbates experimental IBD and that 1,25(OH)2 D3 treatments suppress experimental IBD and other TH 1/TH 17 immune-mediated diseases. There is strong evidence showing a relationship between vitamin D and experimental IBD. In addition, there are several epidemiological studies that showed that low vitamin D status was associated with IBD in humans.20,21 We recently completed a small open-label pilot study in Crohn’s disease patients to determine what dose of vitamin D was needed in humans to raise circulating 25(OH)D3 levels in patients with mild to moderate Crohn’s disease.27 The study determined that most patients required high doses of vitamin D (5000 IU/d) to raise serum 25(OH)D3 levels from below 20 ng/mL to over 40 ng/mL.27 An unexpected effect of the high-dose vitamin D supplementation over 6 months was that patients with mild to moderate disease were in remission at the end of the study.27 The study had several problems that limit the interpretation of the results, including that there was no placebo treatment;27 however, the results do suggest that the data on vitamin D in experimental animals might translate to benefits for patients with IBD. Although we have mainly focused on the effects of vitamin D in IBD, vitamin D may also have protective effects in other chronic immune-mediated diseases and could potentially benefit these patients as well. For example, low levels of vitamin D have also been found in patients with multiple

C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1317 (2014) 70–75 

71

Vitamin D and T cells

Cantorna & Waddell

sclerosis28 and systemic lupus erythematosus,29 and are associated with increased risk for developing type I diabetes.30 Animal models have also been used to demonstrate that 1,25(OH)2 D3 can prevent or ameliorate experimental autoimmune diseases, including autoimmune encephalomyelitis,24 type1 diabetes mellitus,23 autoimmune uveitis,7 and lupus.31 Vitamin D targets in T cells In order to determine the targets of vitamin D in T cells, experiments were done comparing VDR KO and wild-type (WT) T cells. IBD develops in experimental animals when there is an accumulation of TH 1 and TH 17 cells in the gut.32,33 In addition, animals with colitis have few regulatory cells, including FoxP3+ T cells that would normally inhibit pathogenic T cells in the gut.34 The role of the VDR in CD4+ T cells has been reviewed previously.35 Briefly, VDR KO mice have larger numbers of CD4+ T cells with an activated phenotype.36 In addition, Th1 and Th17 cells are over-represented in VDR KO mice, and VDR and vitamin D deficiency resulted in overproduction of IFN-␥ and IL-17 from these cells in the gut.36 Conversely, the number and function of FoxP3+ Treg cells were not different from VDR KO and WT mice.37 However, other nonclassical regulatory T cells, such as invariant natural killer T (NKT) cells, and CD8␣␣/T cell receptor ␣␤ intestinal T cells, were significantly reduced in VDR KO mice.37,38 Vitamin D and 1,25(OH)2 D3 functioned directly to inhibit TH 1 and TH 17 cells. In addition, vitamin D and the VDR are required for the induction of nonclassical regulatory T cells. Together, the evidence shows that vitamin D affects TH cells to induce a balanced T cell response and, as a result, symptoms of experimental IBD improve. Very little has been published on the role of the VDR in CD8+ T cells. Like the CD4+ T cells, CD8+ T cells can either induce disease (contributing to IL17 and IFN-␥ production) or inhibit (CD8␣␤ regulatory cells) IBD.39,40 In addition, CD8+ cells express perforin and granzyme B, which are important for the killing abilities of CD8+ cells. Purified splenic CD8+ T cells from VDR KO, but not WT, mice induced development of experimental IBD in immunodeficient recipients.41 The phenotype of the freshly isolated VDR KO and WT CD8+ T cells were similar with reference to cytokine production, perforin,

72

and granzyme B expression.41 The frequencies of naive cells (CD44+ /CD62L− ) were higher in CD8+ T cells from VDR KO than WT mice.41 In addition, following transfer to immunodeficient recipients, the VDR KO CD8+ T cells produced more IL-17 and IFN-␥ than the WT CD8+ T cells.41 Further experimentation showed that the VDR KO CD8+ T cells proliferated without anti-CD3/CD28 stimulation or upregulation of activation markers in vitro, an effect that was not seen with WT CD8+ T cells.41 Consistent with the in vitro results, in vivo proliferation of CD8+ T cells with a naive phenotype was more rapid with CD8+ T cells from VDR KO mice than with CD8+ T cells from WT mice.41 Therefore, it seems that VDR expression is required to prevent naive CD8+ T cells from expanding. VDR KO CD8+ T cells rapidly proliferated and became pathogenic in the immunodeficient mice, contributing to the development of IBD.41 Paradoxical effects of vitamin D on TH 1 and TH 17 cells T cells that produce IL-17 and IFN-␥ are critical for host protection from infection. Paradoxically, 1,25(OH)2 D3 treatment of mice at doses that inhibit TH 1 and TH 17 cell responses in immune-mediated disease had no effect on the ability of the host to clear a yeast or viral infection.42 In addition, VDR KO mice were able to clear bacterial and parasitic infections with kinetics that were not that different from WT mice.43,44 The ability of vitamin D and 1,25(OH)2 D3 to suppress TH 1 and TH 17 in immune-mediated diseases but not in infectious diseases is paradoxical. In order to understand how VDR deficiency and 1,25(OH)2 D3 treatment affect TH 1 and TH 17 responses in immune-mediated disease but not infectious diseases, we studied the kinetics of T cell production of 1,25(OH)2 D3 and VDR expression.3,45 The VDR is expressed at low levels in freshly isolated CD8+ and CD4+ T cells.2,3,45 Following 24– 48 h of activation and addition of 1,25(OH)2 D3 , the expression of the VDR is induced.2,3,45 In addition, activated CD8+ T cells can produce the enzyme (Cyp27B1) that converts 25(OH)D3 to 1,25(OH)2 D3 .46 In the mouse, it requires 48 h of T cell activation for Cyp27B1 to be expressed by the CD8+ T cells.46 Resting T cells express low levels of the VDR and no Cyp27B1, and only following

C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1317 (2014) 70–75 

Cantorna & Waddell

Vitamin D and T cells

Figure 1. Model of the effects of vitamin D on T cells. In the absence of vitamin D or the VDR, pathogenic T cells become chronically activated and contribute to the development of IBD. Vitamin D functions to turn off T cells directly following activation. 1,25D3 functions to turn off proliferation, IFN-␥, and IL-17. In addition, 1,25D3 induces Treg cells and enhances NKT cell function and CD8␣␣ T cells in the gut. In addition, vitamin D also affects DC maturation and reduces the production of IL-12 that indirectly regulates T cells. Together, vitamin D affects T cell functions, and, in particular, inhibits IFN-␥ and IL-17. The inhibition of TH 17 and TH 1 responses, and the enhanced regulatory cell function restore gastrointestinal homeostasis in the gut.

activation for 24–48 h were the VDR and Cyp27B1 enzyme induced. The regulation of vitamin D responsiveness in T cells is a late event. The ability of vitamin D and 1,25(OH)2 D3 to inhibit T cell proliferation and cytokine production occurs maximally after 48 h of activation. Following an infection, T cells are induced that are important for clearing the pathogen. The effect of vitamin D does not occur until after the T cell response to the infectious organism has begun. In the infection models, the T cells eliminate the pathogen and the antigen is removed from the system. In the immunemediated disease, the antigen persists and the T cells are chronically activated. We propose a new model where vitamin D or VDR deficiency results in the reduced capacity to turn T cells off following activation (Fig. 1). In the infection model, the antigen is eliminated, but in immune-mediated disease such as IBD (as well as other chronic immune-mediated diseases), the antigens persist and the chronically activated T cells proliferate more and over-produce IL-17 and IFN-␥ (Fig. 1).

Conclusions T cells require vitamin D, 1,25(OH)2 D3 , and the VDR to inhibit proliferation and turn off IL-17 and IFN-␥ secretion. Vitamin D is critical for turning T cells off once the antigen has been cleared. Vitamin D–deficient and VDR KO mice are unable to inhibit the proliferation of naive T cells, and in the gut, the T cells develop into cells that produce IL-17 and IFN-␥ and contribute to IBD. Since antigen does not persist following acute infection, the T cells are not chronically activated. Conversely, in diseases such as IBD, antigen persistence results in chronic T cell activation that requires vitamin D and 1,25(OH)2 D3 to turn off the T cells. Conflicts of interest The authors declare no conflicts of interest. References 1. Bhalla, A.K., E.P. Amento, T.L. Clemens, et al. 1983. Specific high-affinity receptors for 1,25-dihydroxyvitamin D3

C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1317 (2014) 70–75 

73

Vitamin D and T cells

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

74

Cantorna & Waddell

in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J. Clin. Endocrinol. Metab. 57: 1308–1310. Provvedini, D.M., C.D. Tsoukas, L.J. Deftos & S.C. Manolagas. 1983. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 221: 1181–1183. Veldman, C.M., M.T. Cantorna & H.F. DeLuca. 2000. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch. Biochem. Biophys. 374: 334–338. Rigby, W.F., T. Stacy & M.W. Fanger. 1984. Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J. Clin. Invest. 74: 1451–1455. Tsoukas, C.D., D.M. Provvedini & S.C. Manolagas. 1984. 1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science 224: 1438–1440. Rigby, W.F., S. Denome & M.W. Fanger. 1987. Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D3. Specific inhibition at the level of messenger RNA. J. Clin. Invest. 79: 1659–1664. Tang, J. et al. 2009. Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. J. Immunol. 182: 4624–4632. Zhu, Y., B.D. Mahon, M. Froicu & M.T. Cantorna. 2005. Calcium and 1alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. Eur. J. Immunol. 35: 217–224. Joshi, S. et al. 2011. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol. Cell. Biol. 31: 3653–3669. Barrat, F.J. et al. 2002. 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. 195: 603– 616. Boonstra, A. et al. 2001. 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J. Immunol. 167: 4974–4980. Sigmundsdottir, H. et al. 2007. DCs metabolize sunlightinduced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8: 285–293. Penna, G. & L. Adorini. 2000. 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164: 2405–2411. Griffin, M.D. et al. 2001. Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 98: 6800–6805. Hugot, J.P. 2004. Inflammatory bowel disease: a complex group of genetic disorders. Best Pract. Res. Clin. Gastroenterol. 18: 451–462. Molodecky, N.A. & G.G. Kaplan. 2010. Environmental risk factors for inflammatory bowel disease. Gastroenterol. Hepatol. 6: 339–346. Sartor, R.B. 2004. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology 126: 1620–1633.

18. Sellon, R.K. et al. 1998. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66: 5224–5231. 19. Nerich, V. et al. 2011. Low exposure to sunlight is a risk factor for Crohn’s disease. Aliment. Pharm. Therap. 33: 940–945. 20. Driscoll, R.H., Jr., S.C. Meredith, M. Sitrin & I.H. Rosenberg. 1982. Vitamin D deficiency and bone disease in patients with Crohn’s disease. Gastroenterology 83: 1252–1258. 21. Mouli, V.P. & A.N. Ananthakrishnan. 2014. Review article: vitamin D and inflammatory bowel diseases. Aliment. Pharm. Therap. 39: 125–136. 22. Cantorna, M.T., C. Munsick, C. Bemiss & B.D. Mahon. 2000. 1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. J. Nutr. 130: 2648–2652. 23. Zella, J.B., L.C. McCary & H.F. DeLuca. 2003. Oral administration of 1,25-dihydroxyvitamin D3 completely protects NOD mice from insulin-dependent diabetes mellitus. Arch. Biochem. Biophys. 417: 77–80. 24. Cantorna, M.T., C.E. Hayes & H.F. DeLuca. 1996. 1,25Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc. Natl. Acad. Sci. U. S. A. 93: 7861–7864. 25. Froicu, M. et al. 2003. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol. Endocrinol. 17: 2386–2392. 26. Froicu, M. & M.T. Cantorna. 2007. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC immunol. 8: 5. 27. Yang, L. et al. 2013. Therapeutic effect of vitamin d supplementation in a pilot study of Crohn’s patients. Clin. Transl. Gastroenterol. 4: e33. 28. Munger, K.L., L.I. Levin, B.W. Hollis, et al. 2006. Serum 25hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296: 2832–2838. 29. Muller, K. et al. 1995. Vitamin D3 metabolism in patients with rheumatic diseases: low serum levels of 25hydroxyvitamin D3 in patients with systemic lupus erythematosus. Clin. Rheumatol. 14: 397–400. 30. Zipitis, C.S. & A.K. Akobeng. 2008. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch. Dis. Child. 93: 512–517. 31. Lemire, J.M., A. Ince & M. Takashima. 1992. 1,25Dihydroxyvitamin D3 attenuates the expression of experimental murine lupus of MRL/l mice. Autoimmunity 12: 143–148. 32. Bouma, G. & W. Strober. 2003. The immunological and genetic basis of inflammatory bowel disease. Nat. Rev. Immunol. 3: 521–533. 33. Abraham, C. & J. Cho. 2009. Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm. Bowel Dis. 15: 1090–1100. 34. Maul, J. et al. 2005. Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology 128: 1868–1878. 35. Ooi, J.H., J. Chen & M.T. Cantorna. 2012. Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors? Mol. Aspects Med. 33: 77–82.

C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1317 (2014) 70–75 

Cantorna & Waddell

36. Bruce, D., S. Yu, J.H. Ooi & M.T. Cantorna. 2011. Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling. Int. Immunol. 23: 519–528. 37. Yu, S., D. Bruce, M. Froicu, et al. 2008. Failure of T cell homing, reduced CD4/CD8alphaalpha intraepithelial lymphocytes, and inflammation in the gut of vitamin D receptor KO mice. Proc. Natl. Acad. Sci. U. S. A. 105: 20834–20839. 38. Yu, S. & M.T. Cantorna. 2008. The vitamin D receptor is required for iNKT cell development. Proc. Natl. Acad. Sci. U. S. A. 105: 5207–5212. 39. Steinhoff, U. et al. 1999. Autoimmune intestinal pathology induced by hsp60-specific CD8 T cells. Immunity 11: 349– 358. 40. Filaci, G. et al. 2004. Nonantigen specific CD8+ T suppressor lymphocytes originate from CD8+ CD28− T cells and inhibit both T-cell proliferation and CTL function. Hum. Immunol. 65: 142–156. 41. Chen, J., D. Bruce & M.T. Cantorna. 2014. Vitamin D receptor expression controls proliferation of naive CD8+ T cells

Vitamin D and T cells

42.

43.

44.

45.

46.

and development of CD8 mediated gastrointestinal inflammation. BMC Immunol. 15: 6. Cantorna, M.T. et al. 1998. 1,25-Dihydroxyvitamin D3 prolongs graft survival without compromising host resistance to infection or bone mineral density. Transplantation 66: 828–831. Bruce, D., J.P. Whitcomb, A. August, et al. 2009. Elevated non-specific immunity and normal Listeria clearance in young and old vitamin D receptor knockout mice. Int. Immunol. 21: 113–122. Whitcomb, J.P. et al. 2012. The role of vitamin D and vitamin D receptor in immunity to leishmania major infection. J. Parasitol. Res. 2012: 134645. Mahon, B.D., A. Wittke, V. Weaver & M.T. Cantorna. 2003. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J. Cell. Biochem. 89: 922–932. Ooi, J.H., K.L. McDaniel, V. Weaver & M.T. Cantorna. 2014. Murine CD8+ T cells but not macrophages express the vitamin D 1alpha-hydroxylase. J. Nutr. Biochem. 25: 58–65.

C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1317 (2014) 70–75 

75

The vitamin D receptor turns off chronically activated T cells.

T cell proliferation and T helper (TH ) cells that make IL-17 (TH 17 cells) and IFN-γ (TH 1 cells) have been shown to be inhibited by 1,25(OH)2 D3 . P...
209KB Sizes 0 Downloads 3 Views