CD4+ICOS+Foxp3+: a sub-population of regulatory T cells contribute to malaria pathogenesis.

BACKGROUND: Regulatory T cells are known to play a key role to counter balance the protective immune response and immune mediated pathology. However, the role of naturally occurring regulatory cells CD4+CD25+Foxp3+ in malaria infection during the disease pathogenesis is controversial. Beside this, ICOS molecule has been shown to be involved in the development and function of regulatory T cell enhance IL-10 production. Therefore, possible involvement of the ICOS dependent regulatory CD4+ICOS+Foxp3+ T cells in resistance/susceptibility during malaria parasite is explored in this study. METHODS: 5 × 105 red blood cells infected with non-lethal and lethal parasites were inoculated in female Balb/c mice by intra-peritoneal injection. Infected or uninfected mice were sacrificed at early (3rd day post infection) and later stage (10th day post infection) of infection. Harvested cells were analysed by using flow cytometer and serum cytokine by Bioplex assay. RESULTS: Thin blood films show that percentages of parasitaemia increases with disease progression in infections with the lethal malaria parasite and mice eventually die by day 14th post-infection. Whereas in case of non-lethal malaria parasite, parasitaemia goes down by 7th day post infection and gets cleared within 13th day. The number of CD4+ ICOS+ T cells increases in lethal infection with disease progression. Surprisingly, in non-lethal parasite, ICOS expression decreases after day 7th post infection as parasitaemia goes down. The frequency of CD4+ICOS+FoxP3+ Tregs was significantly higher in lethal parasitic infection as compared to the non-lethal parasite. The level of IL-12 cytokine was remarkably higher in non-lethal infection compared to the lethal infection. In contrast, the level of IL-10 cytokines was higher in lethal parasite infection compared to the non-lethal parasite. CONCLUSION: Taken together, these data suggest that lethal parasite induce immunosuppressive environment, protecting from host immune responses and help the parasite to survive whereas non-lethal parasite leads to low frequencies of Treg cells seldom impede immune response that allow the parasite to get self-resolved.

IL-10 Producing Regulatory B Cells Mediated Protection against Murine Malaria Pathogenesis.

Various immune cells are known to participate in combating infection. Regulatory B cells represent a subset of B cells that take part in immunomodulation and control inflammation. The immunoregulatory function of regulatory B cells has been shown in various murine models of several disorders. In this study, a comparable IL-10 competent B-10 cell subset (regulatory B cells) was characterized during lethal and non-lethal infection with malaria parasites using the mouse model. We observed that infection of Balb/c mice with P. yoelii I 7XL was lethal, and a rapid increase in dynamics of IL-10 producing B220+CD5+CD1d+ regulatory B cells over the course of infection was observed. However, animals infected with a less virulent strain of the parasite P. yoelii I7XNL attained complete resistance. It was observed that there is an increase in the population of regulatory B cells with an increase of parasitemia; however, a sudden drop in the frequency of these cells was observed with parasite clearance. Adoptive transfer of regulatory B cells to naïve mice followed by infection results in slow parasite growth and enhancement of survival in P. yoelii 17XL (lethal) infected animals. Adoptively transferred regulatory B cells also resulted in decreased production of pro-inflammatory cytokine (IFN-γ) and enhanced production of anti-inflammatory cytokine (IL-10). It infers that these regulatory B cells may contribute in immune protection by preventing the inflammation associated with disease and inhibiting the parasite growth.