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Bacillus Calmette-Guérin Vaccination of Human Newborns Induces T Cells with Complex Cytokine and Phenotypic Profiles¹

Andreia P. Soares^*, Thomas J. Scriba^*, Sarah Joseph^*, Ryhor Harbacheuski, Rose Ann Murray, Sebastian J. Gelderbloem^*, Anthony Hawkridge^*, Gregory D. Hussey^*, Holden Maecker, Gilla Kaplan and Willem A. Hanekom^2,*

^* South African TB/Institute of Infectious Diseases and Molecular Medicine and School of Child and Adolescent Health, Vaccine Initiative, University of Cape Town, Cape Town, South Africa; Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute, Newark, NJ 07103; and BD Biosciences, San Jose, CA 95131

The immune response to vaccination with bacillus Calmette-Guérin (BCG), the only tuberculosis vaccine available, has not been fully characterized. We used multiparameter flow cytometry to examine specific T cell cytokine production and phenotypic profiles in blood from 10-wk-old infants routinely vaccinated with BCG at birth. Ex vivo stimulation of whole blood with BCG for 12 h induced expression of predominantly IFN-, IL-2, and TNF- in CD4⁺ T cells in seven distinct cytokine combinations. IL-4 and IL-10 expression was detected in CD4⁺ T cells at low frequencies and only in cells that did not coexpress type 1 cytokines. Specific CD8⁺ T cells were less frequent than CD4⁺ T cells and produced mainly IFN- and/or IL-2 and less TNF-, IL-4, and IL-10. Importantly, many mycobacteria-specific CD4⁺ and CD8⁺ T cells did not produce IFN-. The predominant phenotype of BCG-specific type 1 T cells was that of effector cells, i.e., CD45RA^–CCR7^–CD27⁺, which may reflect persistence of Mycobacterium bovis BCG in infants until 10 wk of age. Among five phenotypic patterns of CD4⁺ T cells, central memory cells were more likely to be IL-2⁺ and effector cells were more likely to be IFN-⁺. We concluded that neonatal vaccination with BCG induces T cells with a complex pattern of cytokine expression and phenotypes. Measuring IFN- production alone underestimates the magnitude and complexity of the host cytokine response to BCG vaccination and may not be an optimal readout in studies of BCG and novel tuberculosis vaccination.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Aeras Global Tuberculosis Vaccine Foundation and by the European Commission, within the 6th Framework Programme (to A.H., G.D.H., and W.A.H.). T.J.S. is a Wellcome Trust Research Training Fellow (080929/Z/06/Z). G.D.H. is supported by National Institutes of Health Grant D43TW007115, G.K. by National Institutes of Health Grants RO1-AI66046, RO1-AI065653, NO1-AI70022, and RO1-HL55936, and W.A.H. by National Institutes of Health Grants RO1-AI065653 and NO1-AI70022. W.A.H. is also supported by the Bill and Melinda Gates Foundation through Grand Challenges in Global Health Grants 37772 and 37885, the Dana Foundation, and the European and Developing Countries Trials Partnership.

² Address correspondence and reprint requests to Dr. Willem A. Hanekom, University of Cape Town, Health Sciences, Anzio Road, Observatory 7925, South Africa. E-mail address: willem.hanekom{at}uct.ac.za

³ Abbreviations used in this paper: TB, tuberculosis; BCG, bacillus Calmette-Guérin; SEB, streptococcal enterotoxin B.

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