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© The Rockefeller University Press, 0022-1007/1999/10/953/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 7, October 4, 1999 953-962

Tumor Necrosis Factor {alpha} Is a Critical Component of Interleukin 13–mediated Protective T Helper Cell Type 2 Responses during Helminth Infection

David Artisa,c, Neil E. Humphreysa, Allison J. Bancrofta, Nancy J. Rothwellb, Christopher S. Pottenc, and Richard K. Grencisa
a Immunology Group, School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
b Institute of Neuroscience, School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
c Cancer Research Campaign (CRC) Department of Epithelial Biology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 9BX, United Kingdom

Correspondence to: David Artis, Immunology Group, School of Biological Sciences, 3.239 Stopford Building, University of Manchester, Manchester M13 9PT, UK. Tel:44-161-275-5240 Fax:44-161-275-5640 E-mail:mqbsszda{at}man.ac.uk.

In vivo manipulation of cytokine and/or cytokine receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility is associated with a T helper cell type 1 (Th1) cytokine response. Using gene-targeted mice deficient in tumor necrosis factor (TNF) receptor signaling and anti–TNF-{alpha} monoclonal antibody treatment, we have extended these studies to reveal a critical role for TNF-{alpha} in regulation of Th2 cytokine–mediated host protection. In vivo blockade of TNF-{alpha} in normally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the duration of treatment. IL-13–mediated worm expulsion in IL-4 knockout (KO) mice was also shown to be TNF-{alpha} dependent, and could be enhanced by administration of recombinant TNF-{alpha}. Furthermore, TNF receptor KO mice failed to expel T. muris, producing high levels of parasite-specific immunoglobulin G2a and the generation of a predominantly Th1 response, suggesting that the absence of TNF function from the onset of infection dramatically alters the phenotype of the response. These results provide the first demonstration of the role of TNF-{alpha} in regulating Th2 cytokine–mediated responses at mucosal sites, and have implications for the design of rational therapies against helminth infection and allergy.

Key Words: tumor necrosis factor {alpha}, T helper cell type 2 cytokines, helminth infection, interleukin 13, mucosal immunology


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