It is well-recognized that vitamin D3 has immune-modulatory properties and that the variation in ultraviolet (UV) exposure affects vitamin D3 status. Here, we investigated if and to what extent seasonality of vitamin D3 levels are associated with changes in T cell numbers and phenotypes. Every three months during the course of the entire year, human PBMC and whole blood from 15 healthy subjects were sampled and analyzed using flow cytometry. We observed that elevated serum 25(OH)D3 and 1,25(OH)2D3 levels in summer were associated with a higher number of peripheral CD4+ and CD8+ T cells. In addition, an increase in na？ve CD4+CD45RA+ T cells with a reciprocal drop in memory CD4+CD45RO+ T cells was observed. The increase in CD4+CD45RA+ T cell count was a result of heightened proliferative capacity rather than recent thymic emigration of T cells. The percentage of Treg dropped in summer, but not the absolute Treg numbers. Notably, in the Treg population, the levels of forkhead box protein 3 (Foxp3) expression were increased in summer. Skin, gut and lymphoid tissue homing potential was increased during summer as well, exemplified by increased CCR4, CCR6, CLA, CCR9 and CCR7 levels. Also, in summer, CD4+ and CD8+ T cells revealed a reduced capacity to produce pro-inflammatory cytokines. In conclusion, seasonal variation in vitamin D3 status in vivo throughout the year is associated with changes in the human peripheral T cell compartment and may as such explain some of the seasonal variation in immune status which has been observed previously. Given that the current observations are limited to healthy adult males, larger population-based studies would be useful to validate these findings.
References
[1]
Mora JR, Iwata M, von Andrian UH (2008) Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 8: 685–698.
[2]
Bikle D (2009) Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94: 26–34.
[3]
Adams JS, Hewison M (2008) Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 4: 80–90.
[4]
Lips P (2006) Vitamin D physiology. Prog Biophys Mol Biol 92: 4–8.
[5]
Webb AR, Holick MF (1988) The role of sunlight in the cutaneous production of vitamin D3. Annu Rev Nutr 8: 375–399.
[6]
Lips P (2010) Worldwide status of vitamin D nutrition. J Steroid Biochem Mol Biol.
[7]
Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB (2006) Epidemic influenza and vitamin D. Epidemiol Infect 134: 1129–1140.
[8]
Ginde AA, Mansbach JM, Camargo CA Jr (2009) Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med 169: 384–390.
[9]
Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA (2010) Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One 5: e11088.
[10]
Fernandes de Abreu DA, Babron MC, Rebeix I, Fontenille C, Yaouanq J (2009) Season of birth and not vitamin D receptor promoter polymorphisms is a risk factor for multiple sclerosis. Mult Scler 15: 1146–1152.
[11]
Moltchanova EV, Schreier N, Lammi N, Karvonen M (2009) Seasonal variation of diagnosis of Type 1 diabetes mellitus in children worldwide. Diabet Med 26: 673–678.
[12]
Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ (2005) Timing of birth and risk of multiple sclerosis: population based study. BMJ 330: 120.
[13]
Correale J, Ysrraelit MC, Gaitan MI (2009) Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain 132: 1146–1160.
[14]
Simpson S Jr, Blizzard L, Otahal P, van dM I, Taylor B (2011) Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry.
[15]
Zold E, Barta Z, Bodolay E (2011) Vitamin D deficiency and connective tissue disease. Vitam Horm 86: 261–286.
[16]
Veldman CM, Cantorna MT, DeLuca HF (2000) Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 374: 334–338.
[17]
Mahon BD, Wittke A, Weaver V, Cantorna MT (2003) The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J Cell Biochem 89: 922–932.
Tang J, Zhou R, Luger D, Zhu W, Silver PB, Grajewski RS (2009) Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. J Immunol 182: 4624–4632.
[20]
Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A (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.
[21]
Imazeki I, Matsuzaki J, Tsuji K, Nishimura T (2006) Immunomodulating effect of vitamin D3 derivatives on type-1 cellular immunity. Biomed Res 27: 1–9.
[22]
Marelli-Berg FM, Cannella L, Dazzi F, Mirenda V (2008) The highway code of T cell trafficking. J Pathol 214: 179–189.
[23]
Bromley SK, Mempel TR, Luster AD (2008) Orchestrating the orchestrators: chemokines in control of T cell traffic. Nat Immunol 9: 970–980.
[24]
Topilski I, Flaishon L, Naveh Y, Harmelin A, Levo Y (2004) The anti-inflammatory effects of 1,25-dihydroxyvitamin D3 on Th2 cells in vivo are due in part to the control of integrin-mediated T lymphocyte homing. Eur J Immunol 34: 1068–1076.
[25]
Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A (2007) DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat Immunol 8: 285–293.
[26]
Khoo AL, Chai LY, Koenen HJ, Sweep FC, Joosten I, Netea MG, et al. (2011) Regulation of cytokine responses by seasonality of vitamin D status in healthy individuals. Clin Exp Immunol 164: 72–79.
[27]
Moan J, Lagunova Z, Lindberg FA, Porojnicu AC (2009) Seasonal variation of 1,25-dihydroxyvitamin D and its association with body mass index and age. J Steroid Biochem Mol Biol 113: 217–221.
[28]
Van Den Bout-Van Den Beukel CJ, Fievez L, Michels M, Sweep FC, Hermus AR, et al. (2008) Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands: effects of antiretroviral therapy. AIDS Res Hum Retroviruses 24: 1375–1382.
[29]
van Hoof HJ, Swinkels LM, van Stevenhagen JJ, van den BH, Ross HA (1993) Advantages of paper chromatography as a preparative step in the assay of 1,25-dihydroxyvitamin D. J Chromatogr 621: 33–39.
[30]
Anonymous (2011) Seasonal variation of UV index in the Netherlands. http://www.rivm.nl/Onderwerpen/Onderwerp？en/U/UV_ozonlaag_en_klimaat/Zonkracht/Se？izoensvariatie. Date accessed: 11/11/2011.
[31]
Kimmig S, Przybylski GK, Schmidt CA, Laurisch K, Mowes B, Radbruch A, Thiel A (2002) Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J Exp Med 195: 789–794.
[32]
Hollis BW (1996) Assessment of vitamin D nutritional and hormonal status: what to measure and how to do it. Calcif Tissue Int 58: 4–5.
[33]
Alonso A, Hernan MA (2008) Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 71: 129–135.
[34]
Ponsonby AL, McMichael A, van dM I (2002) Ultraviolet radiation and autoimmune disease: insights from epidemiological research. Toxicology 181–182: 71–78.
[35]
Lemire JM, Adams JS, Sakai R, Jordan SC (1984) 1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 74: 657–661.
[36]
Rigby WF, Stacy T, Fanger MW (1984) Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J Clin Invest 74: 1451–1455.
[37]
Muller K, Bendtzen K (1992) Inhibition of human T lymphocyte proliferation and cytokine production by 1,25-dihydroxyvitamin D3. Differential effects on CD45RA+ and CD45R0+ cells. Autoimmunity 14: 37–43.
[38]
Baeke F, Korf H, Overbergh L, van EE, Verstuyf A, Gysemans C, Mathieu C (2010) Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D3 in the immune system. J Steroid Biochem Mol Biol 121: 221–227.
[39]
Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, et al. (2009) 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 183: 5458–5467.
[40]
Smolders J, Thewissen M, Peelen E, Menheere P, Tervaert JW, Damoiseaux (2009) Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS One 4: e6635.
[41]
Morales-Tirado V, Wichlan DG, Leimig TE, Street SE, Kasow KA, Riberdy JM (2011) 1alpha,25-dihydroxyvitamin D3 (vitamin D3) catalyzes suppressive activity on human natural regulatory T cells, uniquely modulates cell cycle progression, and augments FOXP3. Clin Immunol 138: 212–221.
[42]
Mora JR, von Andrian UH (2006) T-cell homing specificity and plasticity: new concepts and future challenges. Trends Immunol 27: 235–243.
[43]
Yamanaka K, Dimitroff CJ, Fuhlbrigge RC, Kakeda M, Kurokawa I, et al. (2008) Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression. J Allergy Clin Immunol 121: 148–157.
[44]
Simpson S Jr, Taylor B, Blizzard L, Ponsonby AL, Pittas F (2010) Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol 68: 193–203.
[45]
Radke KJ, Izzo JL Jr (2010) Seasonal variation in haemodynamics and blood pressure-regulating hormones. J Hum Hypertens 24: 410–416.
[46]
Van Cauter EW, Virasoro E, Leclercq R, Copinschi G (1981) Seasonal, circadian and episodic variations of human immunoreactive beta-MSH, ACTH and cortisol. Int J Pept Protein Res 17: 3–13.
