| Infections with helminth parasites are often characterized by the development of strong Th2 responses that peak during the early acute stage of infection and then decline despite undiminished chronic infection. Through this process of "immunomodulation", Th2-mediated immunopathology is minimized. Previous work suggested that CD25+CD4+ regulatory T (Treg) cells play a critical during Schistosoma mansoni infection. To further address the role of Treg cells, we analyzed Treg cells following host exposure to schistosome eggs, the physiological stimulators of the Th2 response. These studies revealed that Foxp3+Treg cells are activated and proliferate in response to schistosome eggs. In addition, removal of this population resulted in enhanced schistosome egg-specific Th1 and Th2 responses. Given the ability of Treg cells to suppress Th2 responses, we hypothesized that Treg-mediated suppression could account for diminished T cell responsiveness during chronic schistosome infection. Using IL-4-reporter "4get" mice to identify Th2 cells, we found that immunomodulation is not a reflection of the loss of Th2 cells, but rather of the development of hyporesponsiveness within this population. Th2 hyporesponsiveness is apparent early in the response, and becomes more ingrained in response to chronic stimulation with antigen. Contrary to our hypothesis involving Treg suppression, hyporesponsiveness is Th2 cell-intrinsic, and dependent on upregulated expression of the E3 ubiquitin ligase GRAIL. Removal of Th2 cells from antigen results in the downregulation of GRAIL and a dramatic restoration of function. Unexpectedly, hyporesponsive Th2 cells expressed higher levels of IL-7Ralpha and were better equipped to survive in the absence of antigen when compared to the more functional Th2 cells found earlier in infection. Taken together, the data suggests that chronic infection induces the development of hyporesponsive Th2 cells that survive and regain function in the absence of antigen and may provide better protection against reinfection when compared to Th2 cells isolated from the peak of infection. The results described here have implications for helminth infections as well as other Th2-inducing infections and Th2-mediated diseases such as allergy, asthma and ulcerative colitis. |
