CD4⁺T Cell Hyporesponsiveness after Repeated Exposure to Schistosoma mansoni Larvae Is Dependent upon Interleukin-10

Abstract

The effect that multiple percutaneous exposures to Schistosoma larvae has on the development of early CD4+ lymphocyte reactivity is unclear, yet it is important in the context of humans living in areas where schistosomiasis is endemic. In a murine model of multiple infections, we show that exposure of mice to repeated doses (4×) of Schistosoma mansoni cercariae, compared to a single dose (1×), results in CD4+ T cell hyporesponsiveness within the skin-draining lymph nodes (sdLN), manifested as reduced CD4+ cell proliferation and cytokine production. FoxP3+ CD4+ regulatory T cells were present in similar numbers in the sdLN of 4× and 1× mice and thus are unlikely to have a role in effecting hyporesponsiveness. Moreover, anergy of the CD4+ cell population from 4× mice was slight, as proliferation was only partly circumvented through the in vitro addition of exogenous interleukin-2 (IL-2), and the in vivo blockade of the regulatory molecule PD1 had a minimal effect on restoring responsiveness. In contrast, IL-10 was observed to be critical in mediating hyporesponsiveness, as CD4+ cells from the sdLN of 4× mice deficient for IL-10 were readily able to proliferate, unlike those from 4× wild-type cohorts. CD4+ cells from the sdLN of 4× mice exhibited higher levels of apoptosis and cell death, but in the absence of IL-10, there was significantly less cell death. Combined, our data show that IL-10 is a key factor in the development of CD4+ T cell hyporesponsiveness after repeated parasite exposure involving CD4+ cell apoptosis.

Papain‐Based Vaccination Modulates Schistosoma mansoni Infection‐Induced Cytokine Signals

“…For four consecutive experiments, S . mansoni infection was found to induce epidermal cells to release type 1, type 2 and type 17 cytokines, and LNC to produce copious amounts of IFN‐ γ , IL‐4 and IL‐17, 2 and 4 days post‐infection, respectively, likely in response to the enormous amounts of products released by transforming or dying larvae upon skin invasion . These findings do not support the assumption that infection with S .…”

“…These findings do not support the assumption that infection with S . mansoni initially induces immune hyporesponsiveness , as it rather elicits numerous immunologic signals, known to counteract and antagonize each other , resulting into overt immunological chaos. Production of antagonizing immunological signals was also recorded 6–7 days after S .…”

“…As host fate is determined by innate effectors–microbial interactions, intensive studies for more than two decades investigated the initial and early immune response to S . mansoni infection . The cercariae digest the stratum corneum and penetrate the skin via secretions from acetabular glands, the principal source of serine proteases with elastase‐like activity that facilitate penetration of basement membrane of epidermis and underlying dermis .…”

CD4 T‐cell hyporesponsiveness induced by schistosome larvae is not dependent upon eosinophils but may involve connective tissue mast cells

“…This could be related to the decrease in the amount of IL‐10 released in the skin of 4x Mcpt5‐Cre + iDTR + mast cell‐deficient mice leading to enhanced presentation of parasite antigen to CD4 + T cells in the sdLN. Therefore, as CD4 + hyporesponsiveness in the sdLN of 4x mice in our infection model is IL‐10 dependent , and the partial recovery in CD4 + T‐cell responsiveness in the 4x infected Mcpt5Cre iDTR mice was accompanied by a loss in the production of IL‐10, we propose mast cells contribute signals to condition dermal CD4 + T cells in the skin to produce further IL‐10.…”

“…Alternatively, proliferation was measured via incorporation of [ 3 H] thymidine (18Á5 kBq per well, PerkinElmer, Coventry, UK) by sdLN cells cultured in vitro with SSAP antigen as described previously (4,32). Comparable results with regard to CD4 + T-cell proliferation in the sdLN have been obtained previously with CFSE and [ 3 H]thymidine incorporation (4,12).…”