Il-4producing memory T-cells induce alternatively activated macrophages to mediate protection against nematode parasites.

Authors: ANTHONY, ROBERT - USUHS, BETHESDA, MD; Urban, Joseph; ALEM, FARHANG - UMDNJ, NEWARK, NJ; HAMED, HOSSEIN - UMDNJ, NEWARK, NJ; ROZO, C - UMDNJ, NEWARD, NJ; BOUCHER, JEAN-LUC - UNIVRENE DESCARTES,PARIS; VAN ROOIJEN, NICO - VU MED CNTR, AMSTERDAM,N; GAUGE, WILLIAM - UMDNJ, NEWARK, NJ

Submitted to: Nature Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/27/2006
Publication Date: 7/31/2006
Citation: Anthony, R.M., Urban Jr, J.F., Alem, F., Hamed, H.A., Boucher, J., Van Rooijen, N., Gauge, W.C. 2006. IL-4-producing memory T cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nature (Medicine). 12(8):955-960.

Interpretive Summary: The immune response to parasitic worm infection is regulated differently from responses to most bacterial and viral infections because worms invade the tissues and spaces in the body while microbial pathogens often invade cells. Immune mechanisms needed to eliminate different pathogens require different strategies. Nevertheless, nutritional requirements on the immune system can broadly affect function, as in the case of protein deficiencies, or more specifically regulate particular aspects of different host cells that provide effective protection from infection. The macrophage is a cell that can induce protective responses against both intracellular and extracellular pathogens. A determining factor in the control of the choice of the effective mechanism to be employed is the metabolism of an essential amino acid, arginine. Uptake and metabolism of arginine via the enzyme nitric oxide synthase causes increased stores of nitric oxide in the cell that can kill invading microbes. If, however, the pathogen is extracellular, then arginine is metabolized by arginase to produce collagen fibers that tend to contain the parasite in the tissue or prevent unnecessary tissue damage. We have shown that blocking arginase during a worm infection when the parasite is in the tissue of the intestine prevents effective protection and has consequences on intestinal immune function and physiology. This information will be useful to scientists who study the regulation of protective responses to pathogens, and to nutritionists and physiologists who study the nutrient requirements needed to maintain appropriate immune function and tissue repair.

Technical Abstract: Although primary and memory responses against bacteria and viruses have been studied extensively, Th2 effector mechanisms leading to host-protection against helminthic parasites remain elusive. Using a natural murine gastrointestinal nematode parasite model, we characterized the immune cell infiltrate at the host:parasite interface and demonstrated that alternatively activated macrophages dependent on STAT6 signaling preferentially accumulate during the memory but not the primary response. In addition, the alternatively activated macrophages are important effector cells of the protective memory response which contribute to worm expulsion, demonstrating a novel mechanism for host protection against intestinal helminthes. Our studies examined early events in this memory response during larval development in the intestinal submucosa, and showed CD4-dependent responses were essential during these stages of infection; specifically, rapid IL-4 production by memory Th2 cells mediates the accumulation of IL-4R+ alternatively activated macrophages around the invading larvae, which in turn are important for eventual parasite expulsion. Treatment of infected mice with the arginase inhibitor S-(2-boronoethyl)-l-cysteine blocked the protective response indicating that the metabolism of arginine in alternatively activated macrophages regulates a novel effector mechanism in these cells.