Activation of memory Th17 cells by domain 4 pneumolysin in human nasopharynx-associated lymphoid tissue and its association with pneumococcal carriage

Abstract

Pneumococcal carriage is common in children that may account for the high incidence of disease in this age group. Recent studies in animals suggest an important role for CD4+ T cells, T helper type 17 (Th17) cells in particular, in pneumococcal clearance. Whether this Th17-mediated mechanism operates in humans and what pneumococcal components activate Th17 are unknown. We investigated the ability of domain 4 pneumolysin (D4Ply) to activate CD4+ T cells including Th17 in human nasopharynx-associated lymphoid tissue (NALT) and peripheral blood. We show that D4Ply elicited a prominent CD4+ T-cell proliferative response. More importantly, D4Ply elicited a significant memory Th17 response in NALT, and a moderate response in peripheral blood mononuclear cells (PBMCs). This D4Ply-elicited memory Th17 response was more marked in carriage- than in carriage+ children in both NALT and PBMCs. In contrast, no difference was shown in D4Ply-induced Th1 response between the two groups. We also show D4Ply activated human monocytes and murine macrophages that was in part dependent on Toll-like receptor 4 (TLR-4). Our results support a protective role of Th17 against pneumococcal carriage in human nasopharynx, and identify a novel property of D4Ply to activate Th17 in NALT that may offer an attractive vaccine candidate in intranasal immunization against pneumococcal infection.