International Immunology, Vol. 16, No. 1, pp. 43-50,
January 2004
© 2004 Japanese Society for Immunology
Impeded Th1 CD4 memory T cell generation in chronic-persisting liver infection with Echinococcus multilocularis
1 Division of Infectious Diseases and Clinical Immunology and 2 Division of Endocrinology, Department of Internal Medicine, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany
The first two authors contributed equally to this work
Correspondence to: B. J. Manfras; E-mail: burkhard.manfras{at}medizin.uni-ulm.de
Transmitting editor: S. H. E. Kaufmann
Memory T cells of the CD4 lineage coordinate immune responses against pathogens via the antigen-induced secretion of potent effector cytokines. The efficacy of these responses is thought to depend on both the overall number of pathogen-specific memory T cells and the particular array of cytokines that these cells are programmed to secrete. It is unknown to what extent cellular immunity can be induced by Echinococcus multilocularis infection. To examine the immunological memory provided by the adaptive cellular immune system in control of the chronic-persisting infection, peripheral lymphocytes of patients with alveolar echinococcosis (AE) were studied ex vivo. Stimulation of memory cells was performed with E. multilocularis vesicular fluid, purified protein derivative as recall antigen and phytohemagglutinin. Cytomegalovirus latency served as disease control. Frequencies of circulating CD4+ T cells secreting IFN-
, IL-2, tumor necrosis factor-
, IL-4, IL-5 and IL-10 were determined by both cytokine flow cytometry and ELISPOT assays. Most strikingly, in chronic AE the frequencies of E. multilocularis antigen-specific cells committed to Th1-cytokine production were low (mean 0.5% of CD4+ T cells). However, an E. multilocularis-specific response of CD4+ T cells at frequencies of 
0.1% was detected in the majority of AE patients (68%). Low numbers of cells committed to Th1 cytokine secretion were invariably seen in patients with active and inactive disease. Interestingly, the number of specific CD4+ memory T cells was not increased in cured AE patients after complete surgical removal of the metacestode. Hyporesponsiveness during the chronic helminth infection was E. multilocularis specific. Thus, our results demonstrate that antigen-specific memory function against E. multilocularis is markedly different from that against viral or bacterial pathogens. Whether the antigen-specific cellular hyporesponsiveness with impeded Th1 CD4+ memory T cell generation is a cause or a result of the progressive metacestode activity remains to be determined.
Keywords: alveolar echinococcosis, cytokine, cytokine flow cytometry, ELISPOT assay, T cell memory