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Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major

Nature Medicine volume 13, pages 843–850 (2007)Cite this article

Abstract

CD4+ T cells have a crucial role in mediating protection against a variety of pathogens through production of specific cytokines. However, substantial heterogeneity in CD4+ T-cell cytokine responses has limited the ability to define an immune correlate of protection after vaccination. Here, using multiparameter flow cytometry to assess the immune responses after immunization, we show that the degree of protection against Leishmania major infection in mice is predicted by the frequency of CD4+ T cells simultaneously producing interferon-γ, interleukin-2 and tumor necrosis factor. Notably, multifunctional effector cells generated by all vaccines tested are unique in their capacity to produce high amounts of interferon-γ. These data show that the quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.

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Figure 1: Vaccine-elicited protection against L. major.
Figure 2: Multifunctional TH1 cells are optimal effector cells.
Figure 3: CCR7 expression on distinct functional TH1 cells after vaccination.
Figure 4: Prechallenge TH1 functionality predicts protection.
Figure 5: BCG vaccination elicits multifunctional TH1 cells in mice and humans.

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Acknowledgements

TNF-specific antibody (MP6-XT22) was provided by F.D. Finkelman (University of Cincinnati). This research was supported by the Intramural Research Program of the NIH, NIAID.

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Authors and Affiliations

  1. Cellular Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), 40 Convent Drive, Bethesda, 20892, Maryland, USA

    Patricia A Darrah, Dipti T Patel, Paula M De Luca, Ross W B Lindsay, Dylan F Davey, Barbara J Flynn & Robert A Seder

  2. Department of Infectious Disease Immunology, Statens Serum Institute, Artillerivej 5, Copenhagen S, DK-2300, Denmark

    Søren T Hoff & Peter Andersen

  3. Infectious Disease Research Institute, 1124 Columbia Street, Seattle, 98104, Washington, USA

    Steven G Reed

  4. Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Bethesda, 20892, MD, USA

    Sheldon L Morris

  5. ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, 40 Convent Drive, Bethesda, 20892, Maryland, USA

    Mario Roederer

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  1. Patricia A Darrah
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Contributions

P.A.D. designed experiments; developed the multiparameter flow cytometry panel for mice with D.T.P. and M.R.; performed animal studies, intracellular cytokine staining and ELISAs; analyzed and interpreted data; generated figures; and wrote the manuscript with R.A.S. D.T.P assisted in development of the flow cytometry panel, animal studies, intracellular cytokine staining, ELISAs and data analysis. P.M.D.L., R.W.B.L. and D.F.D. assisted in animal studies. B.J.F. performed ELISPOT assays. P.A. provided samples from BCG-vaccinated humans and S.T.H. analyzed these samples with P.A.D. and M.R. S.G.R. provided MML antigen and MML-ADV. S.L.M. provided BCG-vaccinated mice. M.R. assisted in development of the multiparameter flow cytometry panel, data and statistical analysis as well as in preparation of figures and editing of the manuscript. R.A.S. supervised this project, designed experiments, interpreted data and wrote the manuscript with P.A.D.

Corresponding author

Correspondence to Robert A Seder.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Epitope mapping and assessment of inhibitory cytokines following vaccination. (PDF 489 kb)

Supplementary Fig. 2

Functional characterization of distinct populations of Th1 responses using multiparameter flow cytometry (PDF 489 kb)

Supplementary Fig. 3

Magnitude and quality of TH1 responses in lymphoid and non-lymphoid organs after vaccination. (PDF 489 kb)

Supplementary Fig. 4

Proliferative capacity of CD4+ T cells after vaccination. (PDF 489 kb)

Supplementary Fig. 5

Functional hierarchy of TH1 cytokine production in lymphoid and non-lymphoid organs after vaccination. (PDF 489 kb)

Supplementary Fig. 6

Protection in mice after vaccination with high-dose MML-ADV when challenged at the peak of the TH1 response. (PDF 489 kb)

Supplementary Fig. 7

Kinetics and quality of the TH1 influence the degree of protection after infection. (PDF 489 kb)

Supplementary Fig. 8

Durability of TH1 responses after immunization. (PDF 489 kb)

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Darrah, P., Patel, D., De Luca, P. et al. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 13, 843–850 (2007). https://doi.org/10.1038/nm1592

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