IL‐6 promotes CD4⁺ T‐cell and B‐cell activation during Plasmodium infection

Abstract

Humoral immunity develops in the spleen during blood-stage Plasmodium infection. This elicits parasite-specific IgM and IgG, which control parasites and protect against malaria. Studies in mice have elucidated cells and molecules driving humoral immunity to Plasmodium, including CD4 T cells, B cells, interleukin (IL)-21 and ICOS. IL-6, a cytokine readily detected in Plasmodium-infected mice and humans, is recognized in other systems as a driver of humoral immunity. Here, we examined the effect of infection-induced IL-6 on humoral immunity to Plasmodium. Using P. chabaudi chabaudi AS (PcAS) infection of wild-type and IL-6 mice, we found that IL-6 helped to control parasites during primary infection. IL-6 promoted early production of parasite-specific IgM but not IgG. Notably, splenic CD138 plasmablast development was more dependent on IL-6 than germinal centre (GC) B-cell differentiation. IL-6 also promoted ICOS expression by CD4 T cells, as well as their localization close to splenic B cells, but was not required for early Tfh-cell development. Finally, IL-6 promoted parasite control, IgM and IgG production, GC B-cell development and ICOS expression by Tfh cells in a second model, Py17XNL infection. IL-6 promotes CD4 T-cell activation and B-cell responses during blood-stage Plasmodium infection, which encourages parasite-specific antibody production.

Disease severity and blood cytokine concentrations in dogs with natural Babesia rossi infection

“…34 A lot more is known about the role of IL-6 in both human malaria and murine malaria models in which it has been shown to have both protective and pathological effects. 35 In a human study, IL-6 concentrations were proportional to disease severity, being highest in acute cerebral disease and only mildly elevated in uncomplicated disease. 36 MCP-1 has been found to be indicative of the severity of sepsis in humans.…”

“…Very little is known about the role of IL‐6 in canine Babesia infections, yet this cytokine is inversely correlated with T4 and positively correlated with cortisol and both of these hormonal aberrations have been described in canine babesiosis . A lot more is known about the role of IL‐6 in both human malaria and murine malaria models in which it has been shown to have both protective and pathological effects . In a human study, IL‐6 concentrations were proportional to disease severity, being highest in acute cerebral disease and only mildly elevated in uncomplicated disease .…”

Recent Insights into CD4+ Th Cell Differentiation in Malaria

“…Another costimulatory molecule receiving recent attention in malaria, including from our laboratory, has been ICOS (68,71,72). Findings in other models previously indicated B cells express ICOSL at various stages of the humoral response, for example to guide or capture emerging Tfh cells as they move toward B cell follicles (102), and for GC B cells to maintain contact with Tfh cells (90).…”

“…This conundrum now has a solution with the description of Tfh cells in malaria, first in murine models (19), and more recently, in humans (18). These two seminal studies paved the way for an exciting burst of recent studies (14,54,(68)(69)(70)(71)(72)(73)(74), mostly in murine models, although studies in humans are emerging (70). Most recently, evidence now demonstrates an essential role for Tfh cells in resolving bloodstage Plasmodium infections (14,51).…”

“…ICOS was needed for sustaining Tfh and GC B responses, and parasite-specific Ab levels, during the later stages of P. chabaudi and P. yoelii infection in mice, although it was dispensable for early Tfh differentiation (71,72). It should be noted, however, that ICOS upregulation was not restricted to emerging Tfh cells, but was readily and evenly observed on all activated CD4 + T cells (68,71,72), raising the possibility that ICOS signaling might influence all Th fates. Notably, the absence of ICOS-signaling promoted Th1 responses during the first week of infection (71).…”