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.

Vaccination with a live-attenuated small-colony variant improves the humoral and cell-mediated responses against Staphylococcus aureus

“…aureus suggest that vaccine-induced antibodies may be important but frequently appear insufficient for achieving protection against this pathogen [31]. Currently, as perceived from studies in humans and mice [30,32,33], it is assumed that good Th1 and Th17 responses combined to humoral immunity may be required to obtain at least some efficacy against S . aureus , although no specific marker for protection was found thus far [3].…”

The Role of Macrophages in Staphylococcus aureus Infection

“…Newer approaches include targeting S. aureus molecules which stimulate varied immune responses, to mimic the different immune responses observed with natural S. aureus infection. It is now thought that approaches which induce Th1/Th17 responses may be more effective, although this is thought to ideally be best when combined with induction of opsonophagocytic antibody generation ( 439 , 441 ). Many of the aforementioned vaccine studies investigated whether the treatment was able to induce opsonophagocytic killing by phagocytes ( 432 , 433 , 437 , 438 ).…”

CD4+ and CD8+ Circulating Memory T Cells Are Crucial in the Protection Induced by Vaccination with Salmonella Typhi Porins

“…Skin dLN T cells are prone to IFN-γ expression, which is in agreement with previous reports [ 7 ]. On the other hand, although a Th1/Th17 profile following vaccination with bacterial proteins has been described [ 27 ], we found a larger population expressing IL-17 in skin; this particular pattern can be explained because Th17 cells give rise to long-term resident memory T cells following immunization, which can respond immediately against bacterial pathogens [ 28 ].…”