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It is inhibited by the tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2. Deletion of either gene results in robust activation of mTORC1. Mature B cells reside in the spleen at two major anatomical locations, the marginal zone (MZ) and follicles. The MZ constitutes the first line of humoral response against blood\u2010borne pathogens and undergoes atrophy in chronic inflammation. In previous work, we showed that mice deleted for TSC1 in their B cells (TSC1<jats:sup>BKO<\/jats:sup>) have almost no MZ B cells, whereas follicular B cells are minimally affected. To explore potential underlying mechanisms for MZ B\u2010cell loss, we have analysed the spleen MZ architecture of TSC1<jats:sup>BKO<\/jats:sup> mice and found it to be severely impaired. Examination of lymphotoxins (LT<jats:italic>\u03b1<\/jats:italic> and LT<jats:italic>\u03b2<\/jats:italic>) and lymphotoxin receptor (LT<jats:italic>\u03b2<\/jats:italic>R) expression indicated that LT<jats:italic>\u03b2<\/jats:italic>R levels in spleen stroma were reduced by TSC1 deletion in the B cells. Furthermore, LT<jats:italic>\u03b1<\/jats:italic> transcripts in B cells were reduced. Because LT<jats:italic>\u03b2<\/jats:italic>R is sensitive to proteolysis, we analysed cathepsin activity in TSC1<jats:sup>BKO<\/jats:sup>. A higher cathepsin activity, particularly of cathepsin B, was observed, which was reduced by mTORC1 inhibition with rapamycin <jats:italic>in\u00a0vivo<\/jats:italic>. Remarkably, <jats:italic>in\u00a0vivo<\/jats:italic> administration of a pan\u2010cathepsin inhibitor restored LT<jats:italic>\u03b2<\/jats:italic>R expression, LT<jats:italic>\u03b1<\/jats:italic> mRNA levels and the MZ architecture. Our data identify a novel connection, although not elucidated at the molecular level, between mTORC1 and cathepsin activity in a manner relevant to MZ dynamics.<\/jats:p>","DOI":"10.1111\/imm.12996","type":"journal-article","created":{"date-parts":[[2018,8,24]],"date-time":"2018-08-24T09:28:58Z","timestamp":1535102938000},"page":"505-518","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity"],"prefix":"10.1111","volume":"155","author":[{"given":"Naresh Kumar","family":"Meena","sequence":"first","affiliation":[{"name":"Institute for Drug Research The School of Pharmacy The Hebrew University Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakti Prasad","family":"Pattanayak","sequence":"additional","affiliation":[{"name":"Institute for Drug Research The School of Pharmacy 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