Role and plasticity of Th1 and Th17 responses in immunity to Staphylococcus aureus

ABSTRACT

The human commensal Staphylococcus aureus (SA) is a leading cause of skin/soft tissue and surgical-site infections, and bacteremia. Functional antibodies and T-cell-mediated immunity, particularly Th1/Th17 responses, are thought to mediate protection. Vaccine development may be hindered by modulation of vaccine-induced T cells by pathogen-activated immunoregulatory responses, e.g., via IL-10.

We screened SA proteins for CD4⁺ T-cell-activating and IL-10/IL-17-inducing capacities using healthy donor-derived PBMCs. Responses were characterized (Th1/Th17/Th22/immunosuppressive IL-10-producing cells) using intracellular cytokine staining and flow cytometry. Phenotypic plasticity of Th1/Th17 cells was evaluated under pro- or anti-inflammatory conditions using modulatory cytokines. The impact of vaccination on SA-specific memory responses was assessed using samples from a clinical trial evaluating AS03-adjuvanted and non-adjuvanted multicomponent (CPS5/CPS8/α-toxin/ClfA) vaccines (NCT01160172).

The donors exhibited SA-specific memory T-cell responses, indicative of pre-existing immunity to SA. We identified effective activators of Th1 responses (EbhA/IsaA/SdrE/MntC/Aaa/α-toxin), and Th17 and Th1/Th17 responses (EbhA/IsaA/SdrE and, to a lesser extent, α-toxin), but not of Th22 responses or IL-10 production. MRPII, IsdA, and ClfA were inefficient CD4⁺ T-cell activators in our assays. IL-10, likely produced by innate immune cells, influenced mainly Th1 cells by suppressing IFN-γ production. The memory CD4⁺ T-cells observed after long-term stimulation with α-toxin and ClfA indicated that vaccination with these proteins had induced expansion of pre-existing Th1 but not Th17 responses, without apparent adjuvant effect, confirming the trial data. The Th1/Th17-driving proteins (EbhA/IsaA/SdrE) shared low IL-10-promoting abilities and restricted phenotypic plasticity under pro- and anti-inflammatory conditions.

Given the complex immunopathology and multiple virulence factors, identification of Th1/Th17-driving antigens, adjuvants and administration routes, and delineation of the role of memory responses, may advance vaccine development.

KEYWORDS:

• CD4⁺ T cells
• Th17
• anti-bacterial immunity
• commensal
• vaccine
• plasticity

Acknowledgments

The authors are indebted to the participating volunteers, clinicians, nurses, and laboratory technicians of the Phase I vaccine study (NCT01160172³⁰). They also thank Marie-Cécile Mortier, Walthere Dewé, and Cindy Castado (all GSK) for their contributions. Finally, they thank Ellen Oe and Ulrike Krause (both GSK) for scientific writing activities and publication management, respectively.

Authorship Contributions

AF, SB, HW, DB, and RvdM participated in the conception, planning and/or design of the study. AF, SB, PA, and IN participated in the data generation. All authors performed or supervised the data analysis, interpreted the results, and contributed to the development of this manuscript. All authors had full access to the data, gave final approval before submission and agreed to be accountable for all aspects of the work.

Disclosure of potential conflicts of interest

AF, SB, PA, HW, DB, IN, and RvdM are or were at the time of the research work employees of the GSK group of companies. SB, DB and RvdM report ownership of GSK shares and/or restricted GSK shares as part of their employee remuneration.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This study was sponsored by GlaxoSmithKline Biologicals SA, which was involved in all stages of the study conduct and analysis. AF has received funding from the European Union’s FP7 research and innovation programme under the Marie Curie Actions grant agreement No. 330740.