Parasite Immunity Orchestrated by Th2 Cells

Investigator: Richard Locksley, MD
Sponsor: NIH National Institute of Allergy and Infectious Disease

Location(s): United States


Parasitic helminth infections plague billions of persons worldwide and our understanding ofthe host immune response is only rudimentary. Helminthes are vertebrate pathogens and these immune responses can only be understood in the context of the host. Unraveling the pathways involved has great potential to control immune responses not only to helminthes, but also to allergens, which share these types of immunity, with the potential for controlling or treating many important diseases of humans.                                          

Parasitic helminths elicit host immune responses characterized by infiltration of tissues vi/ith Th2 cells, basophils and eosinophils, and the generation of high IgE in serum. These responses reflect stereotyped host mucosal and systemic immunity orchestrated by Th2 cells. Through elaboration of IL-4 and IL-13, Th2 cells organize a focused response necessary to mediate the physiologic alterations ofthe epithelial ban-ier, including enhanced mucus secretion and epithelial cell turnover. Despite these observations, the precise cells which elaborate the IL-4 and IL-13 required to mediate immunity are unknown, and how these cells might contribute to the pathology associated with chronic infestations is poorly understood. We have genetically marked cells that produce IL-4 and, in the last year, IL-13, in the mouse, thus allowing us to follow the cells that contribute these functionally important cytokines. Using infection with Nippostrongylus brasiliensis as well as other challenges, we have begun a systematic dissection ofthe cells and cytokines involved, and of how these cells interact in the relevant tissues. We have managed to generate cell- conditional deletion of IL-4 and IL-13 in important cytokine-producing cells in both the innate and adaptive immune systems. We have also managed conditional deletion of important innate and adaptive cells, including the first demonstration of a basophil-deficient mouse. With these reagents in hand, we are well poised to complete the specific aims of this grant, which remain to use cytokine-function marking to determine (1) which cells are the critical sources of IL-4 and IL-13 in mediating intestinal helminth immunity; (2) which cell types are critical in mediating intestinal helminth immunity; and (3) what is the physical organization of these critical cells and cytokines in tissue that is required to sustain functional Th2-associated immune responses in tissues. These findings will contribute significantly to our understanding of this poorly understood but universal immune response, which is shared by human responses to widely endemic parasitic worms, but also by allergic reactions underlying atopy and asthma.