T Regulatory Cells and BCG as a Vaccine against Tuberculosis: An Overview


Bacille Calmette Guerin (BCG), which has been used since 1921 as the only vaccine against tuber-culosis (TB), protects poorly, if at all, against pulmonary tuberculosis among adults in high incident developing countries. This failure has been attributed to the possible down modulating action of T regulatory cells (Tregs), which can be stimulated by environmental mycobacteria and expanded by BCG vaccination. Tregs induced at the site of BCG vaccination may interfere with protection against tuberculosis. This communication describes the contribution of Tregs towards dampening the efficacy of BCG and plausible approaches to countering this down modulating effect of Tregs. Probably, antigen specific inhibition of the local recruitment of Tregs whilst avoiding generalised disturbance of immune homeostasis could prove to be worthwhile. Alternatively, drugs with short half life may achieve more acceptable transient inhibition of Tregs function than the prolonged action of monoclonal antibodies. Evolving novel safe strategies is a challenge for developing a better anti TB vaccine.

Share and Cite:

Parkash, O. (2015) T Regulatory Cells and BCG as a Vaccine against Tuberculosis: An Overview. World Journal of Vaccines, 5, 96-105. doi: 10.4236/wjv.2015.52012.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] van Crevel, R., Ottenhoff, T.H. and van der Meer, J.W. (2002) Innate immunity to Mycobacterium tuberculosis. Clinical Microbiology Reviews, 15, 294-309.
[2] WHO (2014) Global Tuberculosis Report 2014. WHO/HTM/TB/2014.08, World Health Organization, Geneva.
[3] Zumla, A., Raviglione, M., Hafner, R. and von Reyn, C.F. (2013) Tuberculosis. The New England Journal of Medicine, 368, 745-755.
[4] Ray, S., Talukdar, A., Kundu, S., Khanra, D. and Sonthalia, N. (2013) Diagnosis and Management of Miliary Tuberculosis: Current State and Future Perspectives. Journal of Therapeutics and Risk Management, 9, 9-26.
[5] Narasimhan, P., Wood, J., MacIntyre, C.R. and Mathai, D. (2013) Risk Factors for Tuberculosis. Pulmonary Medicine, 2013, Article ID: 828939.
[6] Lawn, S.D. and Zumla, A.I. (2011) Tuberculosis. The Lancet, 378, 57-72.
[7] Chang, K.-C. and Yew, W.-W. (2013) Management of Difficult Multidrug-Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis: Update 2012. Respirology, 18, 8-21.
[8] TB Alliance: Economic Impact of TB.
[9] Luca, S. and Mihaescu, T. (2013) History of BCG Vaccine. Maedica: A Journal of Clinical Medicine, 8, 53-58.
[10] Andersen, P. and Doherty, T.M. (2005) The Success and Failure of BCG—Implications for a Novel Tuberculosis Vaccine. Nature Reviews Microbiology, 3, 656-662.
[11] Fine, P.E. (1995) Variation in Protection by BCG: Implications of and for Heterologous Immunity. Lancet, 346, 1339-1345.
[12] Ottenhoff, T.H. and Kaufmann, S.H. (2012) Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go? PLoS Pathogens, 8, e1002607.
[13] Fine, P.E., Floyd, S., Stanford, J.L., Nkhosa, P., Kasunga, A., Chaguluka, S., Warndorff, D.K., Jenkins, P.A., Yates, M. and Ponnighaus, J.M. (2001) Environmental Mycobacteria in Northern Malawi: Implications for the Epidemiology of Tuberculosis and Leprosy. Epidemiology and Infection, 126, 379-387.
[14] Brandt, L., Feino Cunha, J., Weinreich Olsen, A., Chilima, B., Hirsch, P., Appelberg, R. and Andersen, P. (2002) Failure of the Mycobacterium bovis BCG Vaccine: Some Species of Environmental Mycobacteria Block Multiplication of BCG and Induction of Protective Immunity to Tuberculosis. Infection and Immunity, 70, 672-678.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC127715/pdf/1144.pdf http://dx.doi.org/10.1128/IAI.70.2.672-678.2002
[15] Ho, P., Wei, X. and Seah, G.T. (2010) Regulatory T Cells Induced by Mycobacterium chelonae Sensitization Influence Murine Responses to Bacille Calmette-Guérin. Journal of Leukocyte Biology, 88, 1073-1080.
[16] Primm, T.P., Lucero, C.A. and Falkinham III, J.O. (2004) Health Impacts of Environmental Mycobacteria. Clinical Microbiology Reviews, 17, 98-106.
[17] Weir, R.E., Black, G.F., Nazareth, B., Floyd, S., Stenson, S., Stanley, C., Branson, K., Sichali, L., Chaguluka, S.D., Donovan, L., Crampin, A.C., Fine, P.E. and Dockrell, H.M. (2006) The Influence of Previous Exposure to Environmental Mycobacteria on the Interferon-Gamma Response to Bacille Calmette-Guérin Vaccination in Southern England and Northern Malawi. Clinical & Experimental Immunology, 146, 390-399.
[18] Parkash, O. (2014) How to Avoid the Impact of Environmental Mycobacteria towards the Efficacy of BCG Vaccination against Tuberculosis? International Journal of Mycobacteriology, 3, 1-4.
[19] Rouanet, C., Debrie, A.S., Lecher, S. and Locht, C. (2009) Subcutaneous Boosting with Heparin Binding Haemagglutinin Increases BCG-Induced Protection against Tuberculosis. Microbes and Infection, 11, 995-1001.
[20] Brandt, L., Skeiky, Y.A., Alderson, M.R., Lobet, Y., Dalemans, W., Turner, O.C., Basaraba, R.J., Izzo, A.A., Lasco, T.M., Chapman, P.L., Reed, S.G. and Orme, I.M. (2004) The Protective Effect of the Mycobacterium bovis BCG Vaccine Is Increased by Coadministration with the Mycobacterium tuberculosis 72-Kilodalton Fusion Polyprotein Mtb72F in M. tuberculosis-Infected Guinea Pigs. Infection and Immunity, 72, 6622-6632.
[21] Reed, S.G., Coler, R.N., Dalemans, W., Tan, E.V., DeLa Cruz, E.C., Basaraba, R.J., Orme, I.M., Skeiky, Y.A., Alderson, M.R., Cowgill, K.D., Prieels, J.P., Abalos, R.M., Dubois, M.C., Cohen, J., Mettens, P. and Lobert, Y. (2009) Defined Tuberculosis Vaccine, Mtb72F/AS02A, Evidence of Protection in Cynomolgus Monkeys. Proceedings of the National Academy of Sciences of the United States of America, 106, 2301-2306.
[22] Rahman, M.J. and Fernandez, C. (2009) Neonatal Vaccination with Mycobacterium bovis BCG: Potential Effects as a Priming Agent Shown in a Heterologous Prime-Boost Immunization Protocol. Vaccine, 27, 4038-4046.
[23] Dietrich, J., Andersen, C., Rappuoli, R., Doherty, T.M., Jensen, C.G. and Andersen, P. (2006) Mucosal Administration of Ag85B-ESAT-6 Protects against Infection with Mycobacterium tuberculosis and Boosts Prior Bacillus Calmette- Guerin Immunity. Journal of Immunology, 177, 6353-6360.
[24] World Health Organization (2004) BCG Vaccine. Weekly Epidemiological Record, 79, 27-38.
[25] Bellet, J.S. and Prose, N.S. (2005) Skin Complications of Bacillus Calmette-Guérin Immunization. Current Opinion in Infectious Diseases, 18, 97-100.
[26] Mills, K.H. (2004) Regulatory T Cells: Friend or Foe in Immunity to Infection? Nature Reviews Immunology, 4, 841-855.
http://www.nature.com/nri/journal/v4/n11/full/nri1485.html http://dx.doi.org/10.1038/nri1485
[27] Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P. and Yamaguchi, T. (2009) Regulatory T Cells: How Do They Suppress Immune Responses? International Immunology, 21, 1105-1111.
[28] Sanchez, A.M. and Yang, Y. (2011) The Role of Natural Regulatory T Cells in Infection. Immunologic Research, 49, 124-134.
[29] Schmitt, E.G. and Williams, C.B. (2013) Generation and Function of Induced Regulatory T Cells. Frontiers in Immunology, 4, 1-13.
[30] Jaron, B., Maranghi, E., Leclerc, C. and Majlessi, L. (2008) Effect of Attenuation of Treg during BCG Immunization on Anti-Mycobacterial Th1 Responses and Protection against Mycobacterium tuberculosis. PLoS ONE, 3, e2833.
[31] Fletcher, H.A., Pathan, A.A., Berthoud, T.K., Dunachie, S.J., Whelan, K.T., Alder, N.C., Sander, C.R., Hill, A.H. and McShane, H. (2008) Boosting BCG Vaccination with MVA85A Down-Regulates the Immunoregulatory Cytokine TGF-Beta1. Vaccine, 26, 5269-5275.
[32] Coleman, M.M., Keane, J. and Mills, K.H. (2010) Editorial: Tregs and BCG—Dangerous Liaisons in TB. Journal of Leukocyte Biology, 88, 1067-1069.
[33] Joosten, S.A. and Ottenhoff, T.H. (2008) Human CD4 and CD8 Regulatory T Cells in Infectious Diseases and Vaccination. Human Immunology, 69, 760-770.
[34] Zuany-Amorim, C., Sawicka, E., Manlius, C., Le Moine, A., Brunet, L.R., Kemeny, D.M., Bowen, G., Rook, G. and Walker, C. (2002) Suppression of Airway Eosinophilia by Killed Mycobacterium vaccae-Induced Allergen-Specific Regulatory T-Cells. Nature Medicine, 8, 625-629.
[35] Quinn, K.M., McHugh, R.S., Rich, F.J., Goldsack, L.M., de Lisle, G.W., Buddle, B.M., Delahunt, B. and Kirman, J.R. (2006) Inactivation of CD4+CD25+ Regulatory T Cells during Early Mycobacterial Infection Increases Cytokine Production but Does Not Affect Pathogen Load. Immunology and Cell Biology, 84, 467-474.
[36] Li, Q. and Shen, H.H. (2009) Neonatal Bacillus Calmette-Guérin Vaccination Inhibits de novo Allergic Inflammatory Response in Mice via Alteration of CD4+CD25+ T-Regulatory Cells. Acta Pharmacologica Sinica, 30, 125-133.
[37] Kim, Y.J., Kim, H.J., Kang, M.J., Yu, H.S., Seo, J.H., Kim, H.Y., Park, S.J., Lee, Y.C. and Hong, S.J. (2014) Bacillus Calmette-Guérin Suppresses Asthmatic Responses via CD4+CD25+ Regulatory T Cells and Dendritic Cells. Allergy Asthma and Immunology Research, 6, 201-207.
[38] Lacan, G., Dang, H., Middleton, B., Horwitz, M.A., Tian, J., Melega, W.P. and Kaufman, D.L. (2013) Bacillus Calmette-Guerin Vaccine-Mediated Neuroprotection Is Associated with Regulatory T-Cell Induction in the 1-methyl-4-phenyl- 1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson’s Disease. Journal of Neuroscience Research, 91, 1292-1302.
[39] Boer, M.C., van Meijgaarden, K.E., Bastid, J., Ottenhoff, T.H. and Joosten, S.A. (2013) CD39 Is Involved in Mediating Suppression by Mycobacterium bovis BCG-Activated Human CD8+CD39+ Regulatory T Cells. European Journal of Immunology, 43, 1925-1932.
[40] Hougardy, J.M., Place, S., Hildebrand, M., Drowart, A., Debrie, A.S., Locht, C. and Mascart, F. (2007) Regulatory T-Cells Depress Immune Responses to Protective Antigens in Active Tuberculosis. American Journal of Respiratory and Critical Care Medicine, 176, 409-416. http://dx.doi.org/10.1164/rccm.200701-084OC
[41] Marin, N.D., París, S.C., Vélez, V.M., Rojas, C.A., Rojas, M. and García, L.F. (2010) Regulatory T Cell Frequency and Modulation of IFN-Gamma and IL-17 in Active and Latent Tuberculosis. Tuberculosis, 90, 252-261.
[42] Sharma, P.K., Saha, P.K., Singh, A., Sharma, S.K., Ghosh, B. and Mitra, D.K. (2009) FoxP3+ Regulatory T Cells Suppress Effector T-Cell Function at Pathologic Site in Miliary Tuberculosis. American Journal of Respiratory and Critical Care Medicine, 179, 1061-1070.
[43] Chen, X., Zhou, B., Li, M., Deng, Q., Wu, X., Le, X., Wu, C., Larmonier, N., Zhang, W., Zhang, H., Wang, H. and Katsanis, E. (2007) CD4+CD25+FoxP3+ Regulatory T Cells Suppress Mycobacterium tuberculosis Immunity in Patients with Active Disease. Clinical Immunology, 123, 50-59.
[44] Guyot-Revol, V., Innes, J.A., Hackforth, S., Hinks, T. and Lalvani, A. (2006) Regulatory T Cells Are Expanded in Blood and Disease Sites in Patients with Tuberculosis. American Journal of Respiratory and Critical Care Medicine, 173, 803-810.
[45] Ribeiro-Rodrigues, R., Resende Co, T., Rojas, R., Toossi, Z., Dietze, R., Boom, W.H., Maciel, E. and Hirsch, C.S. (2006) A Role for CD4+CD25+ T Cells in Regulation of the Immune Response during Human Tuberculosis. Clinical & Experimental Immunology, 144, 25-34.
[46] Li, L., Lao, S.H. and Wu, C.Y. (2007) Increased Frequency of CD4+CD25high Treg Cells Inhibit BCG-Specific Induction of IFN-y by CD4+ T Cells from TB Patients. Tuberculosis, 87, 526-534.
[47] Li, L. and Wu, C.Y. (2008) CD4+CD25+ Treg Cells Inhibit Human Memory yo T Cells to Produce IFN-y in Response to M. tuberculosis Antigen ESAT-6. Blood, 111, 5629-5636.
[48] de Cassan, S.C., Pathan, A.A., Sander, C.R., Minassian, A., Rowland, R., Hill, A.V., McShane, H. and Fletcher, H.A. (2010) Investigating the Induction of Vaccine-Induced Th17 and Regulatory T Cells in Healthy, Mycobacterium bovis BCG-Immunized Adults Vaccinated with a New Tuberculosis Vaccine, MVA85A. Clinical and Vaccine Immunology, 17, 1066-1073.
[49] Griffiths, K.L., Pathan, A.A., Minassian, A.M., Sander, C.R., Beveridge, N.E., Hill, A.V., Fletcher, H.A. and McShane, H. (2011) Th1/Th17 Cell Induction and Corresponding Reduction in ATP Consumption Following Vaccination with the Novel Mycobacterium tuberculosis Vaccine MVA85A. PLoS ONE, 6, e23463.
[50] Luo, Y., Jiang, W., Da, Z., Wang, B., Hu, L., Zhang, Y., An, R., Yu, H., Sun, H., Tang, K., Tang, Z., Wang, Y., Jing, T. and Zhu, B. (2012) Subunit Vaccine Candidate AMM Down-Regulated the Regulatory T Cells and Enhanced the Protective Immunity of BCG on a Suitable Schedule. Scandinavian Journal of Immunology, 75, 293-300.
[51] Fedatto, P.F., Sérgio, C.A., Paula, M.O., Gembre, A.F., Franco, L.H., Wowk, P.F., Ramos, S.G., Horn, C., Marchal, G., Turato, W.M., Silva, C.L., da Fonseca, D.M. and Bonato, V.L. (2012) Protection Conferred by Heterologous Vaccination against Tuberculosis Is Dependent on the Ratio of CD4+/CD4+ Foxp3+ Cells. Immunology, 137, 239-248.
[52] Tameris, M.D., Hatherill, M., Landry, B.S., Scriba, T.J., Snowden, M.A., Lockhart, S., Shea, J.E., McClain, J.B., Hussey, G.D., Hanekom, W.A., Mahomed, H., McShane, H., and the MVA85A 020 Trial Study Team (2013) Safety and Efficacy of MVA85A, a New Tuberculosis Vaccine, in Infants Previously Vaccinated with BCG: A Randomised, Placebo-Controlled Phase 2b Trial. Lancet, 381, 1021-1028.
[53] Bhattacharya, D., Dwivedi, V.P., Kumar, S., Reddy, M.C., Van Kaer, L., Moodley, P. and Das, G. (2014) Simultaneous Inhibition of T Helper 2 and T Regulatory Cell Differentiation by Small Molecules Enhances Bacillus Calmette-Guerin Vaccine Efficacy against Tuberculosis. Journal of Biological Chemistry, 289, 33404-33411.
[54] Rouse, B.T. (2007) Regulatory T Cells in Health and Disease. Journal of Internal Medicine, 262, 78-95.
[55] Torisu, M., Miyahara, T., Shinohara, N., Ohsato, K. and Sonozaki, H. (1978) A New Side Effect of BCG Immunotherapy: BCG Induced Arthritis in Man. Cancer Immunology, Immunotherapy, 5, 77-83.
http://link.springer.com/article/10.1007%2FBF00199980 http://dx.doi.org/10.1007/BF00199980
[56] Shoenfeld, Y. and Isenberg, D.A. (1988) Mycobacteria and Autoimmunity. Immunology Today, 9, 178-182.
[57] Karopoulos, C., Rowley, M.J., Handley, C.J. and Strugnell, R.A. (1995) Antibody Reactivity to Mycobacterial 65 kDa Heat Shock Protein: Relevance to Autoimmunity. Journal of Autoimmunity, 8, 235-248.

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.