Increased vitamin D is associated with decline of naïve, but accumulation of effector, CD8 T cells during early aging


Given the protective roles of 25-hydroxyvitamin D (25(OH)D or vitamin D) in musculoskeletal health and the potential beneficial effects of vitamin D supplementation in reducing the risk of various chronic diseases, intensive repletion of vitamin D has been widely advocated. Of note, CD8 T cells have the highest levels of the vitamin D receptor compared with other major immune cells. The effects of vitamin D on CD8 T cells during aging, however, remain unclear. This study determined the relationship between vitamin D levels and CD8 T cell status in 34 healthy female subjects (all >60 years old). The CD8 T-cell phenotype was defined by the surface expression of CD28 and CD95. The low-25(OH)D serum groups (≤30 ng/ml) had higher percentages of CD28+CD95CD8+ (na?ve) T cells and lower percentages of CD28+CD95+CD8+ (effector) T cells. By contrast, subjects with high levels of 25(OH)D had very low percentages of na?ve CD8 T cells but very high percentages of effector CD8 T cells. There was a significant inverse correlation between 25(OH)D levels and the frequency of na?ve CD8 T cells. The results show that higher levels of vitamin D are correlated with decreased frequencies of na?ve CD8 T cells during early aging, suggesting that higher levels of 25(OH)D accelerate CD8 T cell senescence. These results warrant further evaluation of the effects of vitamin D supplementation in immune aging.

Share and Cite:

Hwang, Y. , Hsu, H. , Lim, F. , Wu, Q. , Yang, P. , Fisher, G. , Hunter, G. and Mountz, J. (2013) Increased vitamin D is associated with decline of naïve, but accumulation of effector, CD8 T cells during early aging. Advances in Aging Research, 2, 72-80. doi: 10.4236/aar.2013.22010.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Gruver, A.L., Hudson, L.L. and Sempowski, G.D. (2007) Immunosenescence of ageing. Journal of Pathology, 211, 144-156. doi:10.1002/path.2104
[2] Hadrup, S.R., Strindhall, J., Kollgaard, T., Seremet, T., Johansson, B., et al. (2006) Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. Journal of Immunology, 176, 2645-2653.
[3] Weng, N.P., Akbar, A.N. and Goronzy, J. (2009) CD28(-) T cells: Their role in the age-associated decline of immune function. Trends in Immunology, 30, 306-312. doi:10.1016/
[4] Weng, N.P. (2008) Telomere and adaptive immunity. Mechanisms of Ageing and Development, 129, 60-66. doi:10.1016/j.mad.2007.11.005
[5] Wilkins, C.H., Sheline, Y.I., Roe, C.M., Birge, S.J. and Morris, J.C. (2006) Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. The American Journal of Geriatric Psychiatry, 14, 1032-1040. doi:10.1097/01.JGP.0000240986.74642.7c
[6] Holick, M.F. (2004) Vitamin D: Importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. The American Journal of Clinical Nutrition, 79, 362-371.
[7] Holick, M.F. (2006) High prevalence of vitamin D inadequacy and implications for health. Mayo Clinic Proceedings, 81, 353-373. doi:10.4065/81.3.353
[8] Buell, J.S., Scott, T.M., Dawson-Hughes, B., Dallal, G.E., Rosenberg, I.H., et al. (2009) Vitamin D is associated with cognitive function in elders receiving home health services. Journal of Gerontology. Series A: Biological Sciences and Medical Sciences, 64, 888-895. doi:10.1093/gerona/glp032
[9] Wei, M.Y., Garland, C.F., Gorham, E.D., Mohr, S.B. and Giovannucci, E. (2008) Vitamin D and prevention of colorectal adenoma: A meta-analysis. Cancer Epidemiology Biomarkers and Prevention, 17, 2958-2969. doi:10.1158/1055-9965.EPI-08-0402
[10] Drechsler, C., Pilz, S., Obermayer-Pietsch, B., Verduijn, M., Tomaschitz, A., et al. (2010) Vitamin D deficiency is associated with sudden cardiac death, combined cardio vascular events, and mortality in haemodialysis patients. European Heart Journal, 31, 2253-2261. doi: 10.1093/eurheartj/ehq246
[11] Grandi, N.C., Breitling, L.P. and Brenner, H. (2010) Vitamin D and cardiovascular disease: Systematic review and meta-analysis of prospective studies. Preventive Medicine, 51, 228-233. doi: 10.1016/j.ypmed.2010.06.013
[12] Pittas, A.G., Lau, J., Hu, F.B. and Dawson-Hughes, B. (2007) The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. Journal of Clinical Endocrinology and Metabolism, 92, 2017-2029. doi:10.1210/jc.2007-0298
[13] Dobnig, H., Pilz, S., Scharnagl, H., Renner, W., Seelhorst, U., et al. (2008) Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Archives of Internal Medicine, 168, 1340-1349. doi:10.1001/archinte.168.12.1340
[14] Bischoff-Ferrari, H.A., Giovannucci, E., Willett, W.C., Dietrich, T. and Dawson-Hughes, B. (2006) Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. The American Journal of Clinical Nutrition, 84, 18-28.
[15] Heaney, R.P. (2009) Optimal vitamin D status. Journal of Bone and Mineral Research, 24, 755. doi:10.1359/jbmr.081219
[16] Holick, M.F. (2007) Vitamin D deficiency. The New Eng land Journal of Medicine, 357, 266-281. doi:10.1056/NEJMra070553
[17] Michaelsson, K., Baron, J.A., Snellman, G., Gedeborg, R., Byberg, L., et al. (2010) Plasma vitamin D and mortality in older men: A community-based prospective cohort study. The American Journal of Clinical Nutrition, 92, 841-848. doi:10.3945/ajcn.2010.29749
[18] Melamed, M.L., Michos, E.D., Post, W. and Astor, B. (2008) 25-hydroxyvitamin D levels and the risk of mortality in the general population. Archives of Internal Medicine, 168, 1629-1637. doi:10.1001/archinte.168.15.1629
[19] Steingrimsdottir, L., Gunnarsson, O., Indridason, O.S., Franzson, L. and Sigurdsson, G. (2005) Relationship be tween serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. The Journal of the American Medical Association, 294, 2336-2341. doi:10.1001/jama.294.18.2336
[20] Sanders, K.M., Stuart, A.L., Williamson, E.J., Simpson, J.A., Kotowicz, M.A., et al. (2010) Annual high-dose oral vitamin D and falls and fractures in older women: A randomized controlled trial. The Journal of the American Medical Association, 303, 1815-1822. doi:10.1001/jama.2010.594
[21] Ohnishi, M., Nakatani, T., Lanske, B., Razzaque, M.S. (2009) Reversal of mineral ion homeostasis and soft tissue calcification of Klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase. Kidney International, 75, 1166-1172. doi:10.1038/ki.2009.24
[22] Forster, R.E., Jurutka, P.W., Hsieh, J.C., Haussler, C.A., Lowmiller, C.L., et al. (2011) Vitamin D receptor controls expression of the anti-aging klothogene in mouse and human renal cells. Biochemical and Biophysical Research Communications, 414, 557-562. doi:10.1016/j.bbrc.2011.09.117
[23] Kato, S., Takeyama, K., Kitanaka, S., Murayama, A., Sekine, K., et al. (1999) In vivo function of VDR in gene expression-VDR knock-out mice. The Journal of Steroid Biochemistry and Molecular Biology, 69, 247-251. doi:10.1016/S0960-0760(99)00042-4
[24] Kamei, Y., Kawada, T., Fukuwatari, T., Ono, T., Kato, S., et al. (1995) Cloning and sequencing of the gene encoding the mouse vitamin D receptor. Gene, 152, 281-282. doi:10.1016/0378-1119(94)00735-B
[25] Veldman, C.M., Cantorna, M.T. and DeLuca, H.F. (2000) Expression of 1,25-dihydroxyvitamin D3 receptor in the immune system. Archives of Biochemistry and Biophysics, 374, 334-338. doi:10.1006/abbi.1999.1605
[26] Von Essen, M.R., Kongsbak, M., Schjerling, P., Olgaard, K., Odum, N., et al. (2010) Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nature Immunology, 11, 344-349. doi:10.1038/ni.1851
[27] Meehan, T.F. and DeLuca, H.F. (2002) The vitamin D receptor is necessary for 1alpha,25-dihydroxyvitamin D3 to suppress experimental autoimmune encephalomyelitis in mice. Archives of Biochemistry and Biophysics, 408, 200-204. doi:10.1016/S0003-9861(02)00580-5
[28] Ross, A.C., Manson, J.E., Abrams, S.A., Aloia, J.F., Brannon, P.M. et al. (2011) The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. The Journal of Clinical Endocrinology and Metabolism, 96, 53-58. doi:10.1210/jc.2010-2704
[29] Tuohimaa, P., Tenkanen, L., Ahonen, M., Lumme, S., Jellum, E. et al. (2004) Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: A longitudinal, nested case-control study in the Nordic countries. International Journal of Cancer, 108, 104-108. doi:10.1002/ijc.11375
[30] Chen, J., Li, J., Lim, F.C., Wu, Q., Douek, D.C., et al. (2010) Maintenance of naive CD8 T cells in nonagenarians by leptin, IGFBP3 and T3. Mechanisms of Ageing and Development, 131, 29-37. doi:10.1016/j.mad.2009.11.003
[31] Rutella, S., Rumi, C., Lucia, M.B., Etuk, B., Cauda, R., et al. (1998) Flow cytometric detection of perforin in normal human lymphocyte subpopulations defined by expression of activation/differentiation antigens. Immunology Letters, 60, 51-55. doi:10.1016/S0165-2478(97)00132-6
[32] Kaech, S.M., Tan, J.T., Wherry, E.J., Konieczny, B.T., Surh, C.D., et al. (2003) Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature Immunology, 4, 1191-1198. doi:10.1038/ni1009
[33] Hsu, H.C., Shi, J., Yang, P., Xu, X., Dodd, C. et al. (2001) Activated CD8(+) T cells from aged mice exhibit decreased activation-induced cell death. Mechanisms of Ageing and Development, 122, 1663-1684. doi:10.1016/S0047-6374(01)00279-2
[34] Hsu, H.C., Scott, D.K., Zhang, P., Zhou, J., Yang, P., et al. (2006) CD8 T-cell immune phenotype of successful aging. Mechanisms of Ageing and Development, 127, 231-239. doi:10.1016/j.mad.2005.10.001
[35] Hunter, G.R., Chandler-Laney, P.C., Brock, D.W., Lara Castro, C., Fernandez, J.R., et al. (2009) Fat Distribution, Aerobic Fitness, Blood Lipids, and Insulin Sensitivity in African-American and European-American Women.
[36] Friedewald, W.T., Levy, R.I. and Fredrickson, D.S. (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical Chemistry, 18, 499-502.
[37] Appay, V., van Lier, R.A., Sallusto, F., Roederer, M. (2008) Phenotype and function of human T lymphocyte subsets: Consensus and issues. Cytometry Part A: The Journal of the International Society for Analytical Cytology, 73, 975-983. doi:10.1002/cyto.a.20643
[38] Murasko, D.M., Weiner, P. and Kaye D. (1987) Decline inmitogen induced proliferation of lymphocytes with increasing age. Clinical and Experimenal Immunology, 70, 440-448.
[39] Eelen, G., Gysemans, C., Verlinden, L., Vanoirbeek, E., De Clercq, P., et al. (2007) Mechanism and potential of the growth-inhibitory actions of vitamin D and analogs. Current Medicinal Chemistry, 14, 1893-1910. doi:10.2174/092986707781058823
[40] Lemire, J.M., Adams, J.S., Sakai, R. and Jordan, S.C. (1984) 1 alpha,25-dihydroxyvitamin D–3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. The Journal of Clinical Investigation, 74, 657-661. doi:10.1172/JCI111465
[41] Goonewardene, I.M. and Murasko, D.M. (1993) Age associated changes in mitogen induced proliferation and cytokine production by lymphocytes of the long-lived brown Norway rat. Mechanisms of Ageing and Development, 71, 199-212. doi:10.1016/0047-6374(93)90084-5
[42] Badovinac, V.P., Messingham, K.A., Jabbari, A., Haring, J.S. and Harty, J.T. (2005) Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination. Nature Medicine, 11, 748-756. doi:10.1038/nm1257
[43] Haring, J.S., Badovinac, V.P. and Harty J.T. (2006) Inflaming the CD8+ T cell response. Immunity, 25, 19-29. doi:10.1016/j.immuni.2006.07.001
[44] Cantorna, M.T., Woodward, W.D., Hayes, C.E. and DeLuca, H.F. (1998) 1,25-dihydroxyvitamin D–3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. Journal of Immunology, 160, 5314-5319.
[45] Rigby, W.F., Denome, S. and Fanger, M.W. (1987) Regulation of lymphokine production and human T lymphocyte activation by 1,25-dihydroxyvitamin D–3. Specific inhibition at the level of messenger RNA. The Journal of Clinical Investigation, 79, 1659-1664. doi:10.1172/JCI113004
[46] Lemire, J.M. (1992) Immunomodulatory role of 1,25 dihydroxyvitamin D3. Journal of Cellular Biochemistry, 49, 26-31. doi:10.1002/jcb.240490106
[47] Tang, J., Zhou, R., Luger, D., Zhu, W., Silver, P.B., et al. (2009) Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. Journal of Immunology, 182, 4624-4632. doi:10.4049/jimmunol.0801543
[48] Ferreira, G.B., van Etten, E., Lage, K., Hansen, D.A., Moreau, Y., et al. (2009) Proteome analysis demonstrates profound alterations in human dendritic cell nature by TX527, an analogue of vitamin D. Proteomics, 9, 3752-3764. doi:10.1002/pmic.200800848
[49] Min, D., Panoskaltsis-Mortari, A., Kuro, O.M., Hollander, G.A., Blazar, B.R., et al. (2007) Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration inmurine models of aging. Blood, 109, 2529-2537. doi:10.1182/blood-2006-08-043794
[50] Wikby, A., Johansson, B., Olsson, J., Lofgren, S., Nilsson, B.O., et al. (2002) Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: The Swedish NONA immune study. Experimental Gerontology, 37, 445-453. doi:10.1016/S0531-5565(01)00212-1
[51] Wikby, A., Ferguson, F., Forsey, R., Thompson, J., Strindhall, J. et al. (2005) An immune risk phenotype, cognitive impairment, and survival in very late life: Impact of allostatic load in Swedish octogenarian and nonagenarian humans. Journal of Gerontology. Series A: Biological Sciences and Medical Sciences, 60, 556-565. doi:10.1093/gerona/60.5.556
[52] Grubeck-Loebenstein, B., Della, B.S., Iorio, A.M., Michel, J.P., Pawelec, G., et al. (2009) Immunosenescence and vaccine failure in the elderly. Aging Clinical and Experimental Research, 21, 201-209.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.