{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:27:32Z","timestamp":1789730852668,"version":"4.0.1"},"reference-count":34,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5545","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2001,11,9]]},"abstract":"<jats:p>\n                    We have identified an alternate developmental pathway in the life cycle of the trematode pathogen\n                    <jats:italic>Schistosoma mansoni<\/jats:italic>\n                    . This pathway is used in immunodeficient hosts in which the parasite fails to receive appropriate signals from the host immune system. Helminth development is altered at an early stage during infection, resulting in the appearance of attenuated forms that prolong survival of host and parasite. Hepatic CD4\n                    <jats:sup>+<\/jats:sup>\n                    T lymphocyte populations are an integral component of the immune signal recognized by the parasite.\n                  <\/jats:p>","DOI":"10.1126\/science.1064462","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T05:37:46Z","timestamp":1027748266000},"page":"1358-1361","source":"Crossref","is-referenced-by-count":123,"title":["Modulation of Blood Fluke Development in the Liver by Hepatic CD4\n                    <sup>+<\/sup>\n                    Lymphocytes"],"prefix":"10.1126","volume":"294","author":[{"given":"Stephen J.","family":"Davies","sequence":"first","affiliation":[{"name":"Tropical Disease Research Unit, Department of Pathology, Veterans Affairs Medical Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane L.","family":"Grogan","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, CA 94143, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca B.","family":"Blank","sequence":"additional","affiliation":[{"name":"Tropical Disease Research Unit, Department of Pathology, Veterans Affairs Medical Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. C.","family":"Lim","sequence":"additional","affiliation":[{"name":"Tropical Disease Research Unit, Department of Pathology, Veterans Affairs Medical Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Locksley","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, CA 94143, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James H.","family":"McKerrow","sequence":"additional","affiliation":[{"name":"Tropical Disease Research Unit, Department of Pathology, Veterans Affairs Medical Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/365797a0"},{"key":"e_1_3_1_3_2","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1098\/rspb.2000.1249","volume":"267","author":"Harvey S. C.","year":"2000","unstructured":"Harvey S. C., Gemmill A. W., Read A. F., Viney M. E., Proc. R. Soc. Biol. Sci. Ser. B 267, 2057 (2000).","journal-title":"Proc. R. Soc. Biol. Sci. Ser. B"},{"key":"e_1_3_1_4_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S1471-4922(00)01835-3","volume":"17","author":"Ravindran B.","year":"2001","unstructured":"Ravindran B., Trends Parasitol. 17, 70 (2001).","journal-title":"Trends Parasitol."},{"key":"e_1_3_1_5_2","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1017\/S0031182000050629","volume":"86","author":"Harrison R. A.","year":"1983","unstructured":"Harrison R. A., Doenhoff M. J., Parasitology 86, 429 (1983).","journal-title":"Parasitology"},{"key":"e_1_3_1_6_2","doi-asserted-by":"crossref","unstructured":"P. Amiri et al. Nature 356 604 (1992).","DOI":"10.1038\/356604a0"},{"key":"e_1_3_1_7_2","unstructured":"Puerto Rican strain S. mansoni were maintained in the laboratory with the use of Syrian golden hamsters and Biomphalaria glabrata snails as hosts. RAG-1 \u2212\/\u2212 mice were purchased from Jackson Laboratory (Bar Harbor ME). C57BL\/6 mice were purchased from Charles River (Wilmington MA). All animals were housed at the San Francisco Veteran Affairs Medical Center in accordance with protocols approved by the Institutional Animal Care and Use Committee. Mice were infected by exposure of the tail skin to 100 to 150 cercariae. Parasites were recovered from the portal system at various time points p.i. by perfusion immediately fixed in 4% buffered formaldehyde and photographed using a Nikon Microphot (Melville NY) microscope at 25\u00d7 magnification."},{"key":"e_1_3_1_8_2","doi-asserted-by":"crossref","unstructured":"P. Mombaerts et al. Cell 68 869 (1992).","DOI":"10.1016\/0022-3913(92)90227-2"},{"key":"e_1_3_1_9_2","unstructured":"Oncomelania hupensis infected with S. japonicum were obtained from F. A. Lewis (Biomedical Research Institute Rockville MD). RAG-2 \u2212\/\u2212 and wild-type BALB\/c mice were purchased from Taconic (Germantown NY)."},{"key":"e_1_3_1_10_2","unstructured":"S. J. Davies et al. unpublished data."},{"key":"e_1_3_1_11_2","doi-asserted-by":"crossref","unstructured":"K. Dorshkind et al. J. Immunol. 132 1804 (1984).","DOI":"10.4049\/jimmunol.132.4.1804"},{"key":"e_1_3_1_12_2","unstructured":"To determine liver egg burdens \u223c100 mg of liver tissue from the margin of the left lobe was digested in 0.7 % trypsin (50 ml) in phosphate-buffered saline (PBS) for 1 hour at 37\u00b0C and eggs were counted under a dissecting microscope."},{"key":"e_1_3_1_13_2","unstructured":"No developmental or egg-laying defects were observed in TNF \u2212\/\u2212 TNF \u2212\/\u2212 \/lymphotoxin (LT)-\u03b1 \u2212\/\u2212 or TNFR-1 \u2212\/\u2212 \/TNFR-2 \u2212\/\u2212 mice (9) indicating that parasite development was not dependent on these cytokines or downstream effects of TNFR signaling."},{"key":"e_1_3_1_14_2","unstructured":"Normal parasite development was observed in interferon (IFN)-\u03b3 \u2212\/\u2212 mice (S. J. Davies K. C. Lim J. H. McKerrow unpublished data) interleukin (IL)-4 \u2212\/\u2212 and IL-5 \u2212\/\u2212 mice (L. Rosa-Brunet personal communication) and in signal transducer and activator of transcription (STAT)-4 \u2212\/\u2212 and STAT-6 \u2212\/\u2212 mice (R. B. Blank K. C. Lim S. J. Davies J. H. McKerrow unpublished data)."},{"key":"e_1_3_1_15_2","doi-asserted-by":"crossref","unstructured":"I. Wolowczuk et al. Infect. Immun. 67 4183 (1999).","DOI":"10.1128\/IAI.67.8.4183-4190.1999"},{"key":"e_1_3_1_16_2","doi-asserted-by":"crossref","unstructured":"U. von Freeden-Jeffry et al. J. Exp. Med. 181 1519 (1995).","DOI":"10.1084\/jem.181.4.1519"},{"key":"e_1_3_1_17_2","doi-asserted-by":"crossref","unstructured":"J. J. Peschon et al. J. Exp. Med. 180 1955 (1994).","DOI":"10.1084\/jem.180.5.1955"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/350423a0"},{"key":"e_1_3_1_19_2","doi-asserted-by":"crossref","unstructured":"P. Mombaerts et al. Nature 360 225 (1992).","DOI":"10.1038\/360225a0"},{"key":"e_1_3_1_20_2","doi-asserted-by":"crossref","unstructured":"S. Itohara et al. Cell 72 337 (1993).","DOI":"10.1016\/0092-8674(93)90112-4"},{"key":"e_1_3_1_21_2","unstructured":"Igh-6 \u2212\/\u2212 TCR\u03b2 \u2212\/\u2212 TCR\u03b4 \u2212\/\u2212 and TCR\u03b2 \u2212\/\u2212 \/TCR\u03b4 \u2212\/\u2212 mice were purchased from Jackson Laboratory."},{"key":"e_1_3_1_22_2","doi-asserted-by":"crossref","unstructured":"D. Jankovic et al. J. Exp. Med. 187 619 (1998).","DOI":"10.1084\/jem.187.4.619"},{"key":"e_1_3_1_23_2","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1002\/eji.1830250404","volume":"25","author":"Iacomini J.","year":"1995","unstructured":"Iacomini J., Ricklan D. E., Stadecker M. J., Eur. J. Immunol. 25, 884 (1995).","journal-title":"Eur. J. Immunol."},{"key":"e_1_3_1_24_2","unstructured":"For reconstitution experiments lymph nodes from wild type C57BL\/6 mice were dispersed through a 70-\u03bcm nylon strainer and cells were labeled with fluorescein isothiocyanate (FITC)\u2013conjugated antibodies to CD8 and phycoerythrin (PE)-conjugated antibodies to CD19 (BD Pharmingen San Diego CA) and Alexa-conjugated antibodies to CD4 (Molecular Probes Eugene OR). CD8 + CD19 + or CD4 + cells were sorted to >99% purity after gating small resting cells using forward- and side-scatter parameters (MoFlo Multi-Laser Flow Cytometer; Cytomation Fort Collins CO). 4 \u00d7 10 6 cells were transferred into RAG-1 \u2212\/\u2212 mice by intravenous injection. Control mice received PBS alone. At necropsy splenocytes from reconstituted RAG-1 \u2212\/\u2212 mice were surface labeled with tricolor (TC)-conjugated antibodies to CD4 (Santa Cruz Biotechnologies Santa Cruz CA) FITC-conjugated antibodies to CD8 and PE-conjugated antibodies to CD19 and analyzed using a FACScalibur flow cytometer with CellQuest software (Becton Dickinson Franklin Lakes NJ)."},{"key":"e_1_3_1_25_2","unstructured":"Antibodies used for depletion experiments were: GK1.5 (antibody to CD4; ATCC TIB-207); 3.155 (antibody to CD8; ATCC TIB-211); GL-3 (antibody to TCR\u03b3\u03b4). Antibodies were purified by affinity chromatography and administered by intraperitoneal injection twice weekly at a dose of 1 mg per animal beginning 1 week before infection and continuing until necropsy."},{"key":"e_1_3_1_26_2","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/0014-4894(65)90037-8","volume":"16","author":"Clegg J. A.","year":"1965","unstructured":"Clegg J. A., Exp. Parasitol. 16, 133 (1965).","journal-title":"Exp. Parasitol."},{"key":"e_1_3_1_27_2","unstructured":"Supplementary material is available at Science Online at www.sciencemag.org\/cgi\/content\/full\/294\/5545\/1358\/DC1."},{"key":"e_1_3_1_28_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1034\/j.1600-0528.2002.017415.x","volume":"174","author":"Abo T.","year":"2000","unstructured":"Abo T., Kawamura T., Watanabe H., Immunol. Rev. 174, 135 (2000).","journal-title":"Immunol. Rev."},{"key":"e_1_3_1_29_2","doi-asserted-by":"crossref","unstructured":"M. Zijlstra et al. Nature 344 742 (1990).","DOI":"10.1038\/344742a0"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1910207"},{"key":"e_1_3_1_31_2","unstructured":"\u03b22-m \u2212\/\u2212 and MHC II \u2212\/\u2212 mice were purchased from Jackson Laboratory and Taconic respectively. At necropsy livers were dispersed into single cell suspensions like spleens but a 30% percoll gradient was used to separate hepatocytes from hepatic leukocytes before staining for cell surface molecules. Organs from at least three animals of each genotype and infection state were pooled for analysis. Cells were stained in the presence of unlabeled monoclonal antibodies to CD16 and CD32 (\u201cFc Block\u201d; BD Pharmingen). Analysis was performed on a FACScan flow cytometer using CellQuest."},{"key":"e_1_3_1_32_2","unstructured":"Flow cytometric analyses were performed using a MoFlo Multi-Laser Flow Cytometer Alexa350-conjugated antibodies to CD4 allophycocyanin (APC)-conjugated antibodies to TCR\u03b2 and the following additional antibodies all in the presence of \u201cFc Block\u201d: FITC-conjugated antibodies to CD3 or antibodies to DX5 PE-conjugated antibodies to Thy-1 or antibodies to Ly-49A\/C\/D and TC-conjugated CD5 or NK1.1."},{"key":"e_1_3_1_33_2","unstructured":"For V \u03b2 analysis cells were stained with CyChrome-conjugated antibodies to CD4 PE-conjugated antibodies to CD11b and FITC-conjugated antibodies to V \u03b2 in the presence of \u201cFc Block.\u201d Binding of antibody to V \u03b2 binding was determined on the CD4 + CD11b \u2212 population. Percentages were calculated by comparison with binding by a pan-TCR\u03b2-specific antibody. Antibodies to V \u03b2 >17a were included as a negative control because C57BL animals do not express V \u03b2 >17a."},{"key":"e_1_3_1_34_2","doi-asserted-by":"crossref","first-page":"515","DOI":"10.4269\/ajtmh.1997.56.515","volume":"56","author":"Karanja D. M.","year":"1997","unstructured":"Karanja D. M., Colley D. G., Nahlen B. L., Ouma J. H., Secor W. E., Am. J. Trop. Med. Hyg. 56, 515 (1997).","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"e_1_3_1_35_2","unstructured":"We thank C. Franklin and C. McArthur for technical assistance; K. A. Feldman for assistance with statistical analyses; L. Rosa-Brunet for communicating unpublished data; J. D. Sedgwick for TNF \u2212\/\u2212 and TNF \u2212\/\u2212 \/LT \u2212\/\u2212 mice; G. Yap for TNFR1 \u2212\/\u2212 \/TNFR2 \u2212\/\u2212 mice; L. Lefrancois for the GL-3 anti-\u03b3\u03b4TCR hybridoma; and L. Rosa-Brunet C. R. Caffrey J. P. Salter G. Gr\u00fcnig K. Shinkai J. C. Ryan M. Dawes L. L. Lanier and J. A. Glaven for helpful discussions and advice. Microscopy was performed at the UCSF Liver Center Microscopy Core. Supported by National Institutes of Health grant AI10424 (to S.J.D.) and the Sandler Family Foundation (to J.H.M.)."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.1064462","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T17:38:08Z","timestamp":1704821888000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.1064462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,11,9]]},"references-count":34,"journal-issue":{"issue":"5545","published-print":{"date-parts":[[2001,11,9]]}},"alternative-id":["10.1126\/science.1064462"],"URL":"https:\/\/doi.org\/10.1126\/science.1064462","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1002959.31456","asserted-by":"object"}]},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,11,9]]}}}