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Originally published online as doi:10.2353/ajpath.2009.090137 on July 23, 2009

Published online before print July 23, 2009
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(American Journal of Pathology. 2009;175:706-716.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090137

IL-4R{alpha} Responsiveness of Non-CD4 T Cells Contributes to Resistance in Schistosoma mansoni Infection in Pan-T Cell-Specific IL-4R{alpha}-Deficient Mice

Benjamin Dewals, Jennifer C. Hoving, Mosiuoa Leeto, Reece G. Marillier, Umeshree Govender, Antony J. Cutler, William G.C. Horsnell and Frank Brombacher

From the International Centre for Genetic Engineering and Biotechnology and Institute of Infectious Disease and Molecular Medicine, Division of Immunology, University of Cape Town, Cape Town, South Africa

Interleukin (IL)-4 and IL-13 are T helper 2 cytokines whose biological functions are induced through a common IL-4 receptor {alpha} chain (IL-4R{alpha}). CD4+ T cell-specific IL-4R{alpha}-mediated signaling drives susceptibility to Leishmania major infection, but is not essential to host survival following Schistosoma mansoni infection. Here we generated a novel mouse model lacking IL-4R{alpha} expression specifically on all T cells (iLckcreIl4ra–/lox), which was compared with CD4+ T cell-specific IL-4R{alpha}-deficient mice (LckcreIl4ra–/lox), to investigate the possible roles of IL-4R{alpha} responsive non-CD4+ T cells during either L. major or S. mansoni infection. Our results demonstrate a successful generation of transgene-bearing hemizygous iLckcreIl4ra–/lox BALB/c mice that have effective deletion of IL-4R{alpha} on all T-cell populations. We show that iLckcreIl4ra–/lox mice infected with L. major developed a healing disease phenotype as previously observed in LckcreIl4ra–/lox mice, demonstrating that absence of IL-4R{alpha}-responsive non-CD4+ in addition to CD4+ T cells does not further affect transformation of BALB/c to a healer phenotype. In acute schistosomiasis, however, iLckcreIl4ra–/lox mice showed enhanced mortality compared with Il4ra–/lox and LckcreIl4ra–/lox mice. iLckcreIl4ra–/lox mice died with similar kinetics to highly susceptible Il4ra–/– mice, despite controlling gut inflammation. In addition, iLckcreIl4ra–/lox mice presented increased liver granuloma sizes, as compared with LckcreIl4ra–/lox mice, with similar eosinophils, fibrosis, and liver damage. In conclusion, IL-4R{alpha}-responsive non-CD4+ T cells prolong survival to acute schistosomiasis and contribute to the better control of hepatic granulomatous inflammation.






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