Urokinase-deficient mice fail to generate a type 2 immune response following schistosomal antigen challenge.
Activated lymphocytes express urokinase-type plasminogen activator (uPA). Previous work suggests that uPA modulates T-lymphocyte responses. Mice deficient in uPA (uPA(-/-)) fail to generate type 1 (T1) immune responses during infection with Cryptococcus neoformans. Failure to generate either a T1 or a T2 immune response is not predictive of defects in the alternative response. Conversely, down-regulation of one type of immune response may result in inappropriate overactivation of the other. It is not known whether the immune defect in uPA(-/-) mice affects only T1 responses or whether T2 responses are also impaired. Impairment of both T1 and T2 responses would suggest a global T-cell defect in the absence of uPA. To determine the role of uPA in T2 immune responses, wild-type (WT) and uPA(-/-) mice were primed and challenged with schistosomal egg antigen (SEA). This elicits strong polarization to T2 immune responses in immunocompetent mice. The challenged WT mice developed delayed-type hypersensitivity (DTH) to SEA; high levels of serum immunoglobulin E (IgE); a strong T2 cytokine phenotype with markedly elevated levels of interleukin-4 (IL-4), IL-5, and IL-13; and eosinophil-rich pulmonary granulomas. uPA(-/-) mice failed to develop DTH to SEA; did not polarize Ig production to IgE; did not produce high levels of IL-4, IL-5, or IL-13; and had markedly reduced numbers of granuloma-associated eosinophils. uPA(-/-) mice fail to generate polarized T2 immune responses to a T2-inducing pathogen. These findings, in conjunction with our previous work, demonstrate that mice deficient in uPA have profoundly impaired immunity involving both T1 and T2 polarization and are largely immunologically unresponsive.
Gyetko
Margaret R
MR
Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System and University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA. mgyetko@umich.edu
Sud
Sudha
S
Chensue
Stephen W
SW
D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D015769:Granuloma, Respiratory Tract / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000209:etiology; D007073:Immunoglobulin E / Q000097:blood; D008213:Lymphocyte Activation; D051379:Mice; D012547:Schistosoma / Q000276:immunology*; D012552:Schistosomiasis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000378:metabolism*
D000947:Antigens, Helminth; D016207:Cytokines; D007073:Immunoglobulin E; D014568:Urokinase-Type Plasminogen Activator