Regulatory issues in immunity to liver and blood-stage malaria

Protective immunity differs between routes of administration of attenuated malaria parasites independent of parasite liver load

“…Improved clearance of iRBCs has been observed in the absence of Treg-derived IL-10 71 , 72 . Only few studies have addressed regulatory cells after immunization 71 , 73 , 74 . Unfortunately, those studies do not provide insight whether the observed regulatory responses are only a consequence of blood stage infections or can already be induced by the pre-erythrocytic stages, i.e.…”

Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4

“…Though the mechanism behind this hiatus in Th cell expansion has remained unknown, we perceived it as a tangible sign of the general immunosuppression associated with blood-stage malaria. This assumption was underscored by the consistently observed increase in the key immunosuppressive cell population: Foxp3 + Tregs, during blood-stage malaria in humans (Supplementary table 1) and mice (Figure 1A–D), as well as the numerical and functional correlation between Tregs and disease susceptibility 5,8,9 . Higher parasite densities in blood were associated with higher Treg frequencies in humans; and chloroquine treatment to decrease parasitemia reduced Treg frequencies in mice (Supplementary figure 3A–B), also tempering the drop in Th frequencies (Supplementary figure 3C).…”

“…Despite mounting substantial T and B cell responses, humans fail to efficiently control blood-stage malaria or develop sterilizing immunity to reinfections 2 . Though Foxp3 + regulatory T cells (Tregs) form a part of these responses 3–5 , their influence remains disputed, and mode of action unknown. Here we show that Tregs, which expand in both humans and rodents during blood-stage malaria, interfere with conventional T helper (Th) cell responses and the Follicular T helper (Tfh) cell:B cell partnership in germinal centers, in a critical temporal window to impede protective immunity, through the Cytotoxic T-lymphocyte-Associated protein (CTLA)-4.…”

“…Higher parasite densities in blood were associated with higher Treg frequencies in humans; and chloroquine treatment to decrease parasitemia reduced Treg frequencies in mice (Supplementary figure 3A–B), also tempering the drop in Th frequencies (Supplementary figure 3C). The impact and function of Tregs in malaria has remained controversial 5,10,11 , with independent studies suggesting that Tregs suppress 8,12,13 , or enhance 14,15 protection in this infection. While some concluded that depleting Tregs helped control parasitemia, disease severity or morality 8,12,16 , others saw no impact 14,17,18 or even increased parasitemia and disease severity in some cases 15 .…”

Profiling MHC II immunopeptidome of blood‐stage malaria reveals that cDC 1 control the functionality of parasite‐specific CD 4 T cells

“…In malaria‐endemic areas, a nagging issue is the failure of naturally exposed individuals to develop sterile long‐lasting protective immunity. This may be due to several factors including the stage specificity of parasite antigen expression, the antigenic variability among field parasites, and the profound immune dysregulation caused by pre‐erythrocytic and erythrocytic stages (Renia & Goh, ; Scholzen & Sauerwein, ; Van Braeckel‐Budimir et al , ). These factors could also contribute to explain why despite tremendous investments and years of research, progress on the vaccination front has been only modest.…”