Murine schistosomiasis mansoni: coordinate cytokine regulation and differences in cellular immune responses of granuloma cells and splenocytes to endogenous and exogenous schistosome egg antigens.

To better understand the cellular immune mechanisms that regulate granulomatous inflammation to Schistosoma mansoni ova, we examined the dynamics of lymphocyte proliferation and cytokine expression by granuloma cells and splenocytes to endogenous and exogenous schistosome egg antigen (SEA) 6-19 weeks postinfection. Compared to splenocytes, granuloma cells (partially CD4+ cells) which are at the site of antigen release were highly activated by endogenous SEA and terminally differentiated as indicated by the more than 10-fold greater frequency of ex vivo interleukin (IL)-4, IL-5 and interferon (IFN)-gamma -secreting cells, greater levels of constitutive cytokine production and failure to proliferate to either endogenous or exogenous SEA. Endogenous cytokine production by granuloma cells was coordinately regulated, enhanced little by exogenous SEA, and temporally correlated with granulomatous inflammation. By contrast, CD4+ splenocytes produced comparatively little cytokine release by endogenous antigen, whereas exogenous SEA strongly induced IL-4, IL-5, IL-10 and IFN-gamma production and lymphocyte proliferation that correlated poorly with the dynamics of granulomatous inflammation. These results show that cytokine responses to endogenous SEA correlated better with granulomatous inflammation than responses to exogenous SEA. Furthermore, granuloma cells and splenocytes demonstrated strikingly different proliferative responses and dynamics of cytokine expression, suggesting that how SEA reactive lymphocytes traffic between lymphoid tissues and the granuloma is critical to a better understanding of the mechanisms of granulomatous inflammation and its modulation.