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-, 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-. 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 (T_H1) cells.

1. Cellular Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), 40 Convent Drive, Bethesda, Maryland 20892, USA.
2. Department of Infectious Disease Immunology, Statens Serum Institute, Artillerivej 5, DK-2300 Copenhagen S, Denmark.
3. Infectious Disease Research Institute, 1124 Columbia Street, Seattle, Washington 98104, USA.
4. Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Bethesda, MD 20892, USA.
5. ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, 40 Convent Drive, Bethesda, Maryland 20892, USA.

Correspondence to: Robert A Seder¹ e-mail: rseder@mail.nih.gov

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