mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity
Author(s) -
Meeresh Kumar,
Pattanayak Shakti Prasad,
BenNun Yael,
Benhamron Sandrine,
Kumar Saran,
Merquiol Emmanuelle,
Hövelmeyer Nadine,
Blum Galia,
Tirosh Boaz
Publication year - 2018
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12996
Subject(s) - mtorc1 , biology , cathepsin , cathepsin l , spleen , cathepsin b , cathepsin s , marginal zone , pi3k/akt/mtor pathway , microbiology and biotechnology , b cell , immunology , signal transduction , biochemistry , antibody , enzyme
Summary Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell metabolism and lymphocyte proliferation. 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‐borne pathogens and undergoes atrophy in chronic inflammation. In previous work, we showed that mice deleted for TSC1 in their B cells (TSC1 BKO ) have almost no MZ B cells, whereas follicular B cells are minimally affected. To explore potential underlying mechanisms for MZ B‐cell loss, we have analysed the spleen MZ architecture of TSC1 BKO mice and found it to be severely impaired. Examination of lymphotoxins (LT α and LT β ) and lymphotoxin receptor (LT β R) expression indicated that LT β R levels in spleen stroma were reduced by TSC1 deletion in the B cells. Furthermore, LT α transcripts in B cells were reduced. Because LT β R is sensitive to proteolysis, we analysed cathepsin activity in TSC1 BKO . A higher cathepsin activity, particularly of cathepsin B, was observed, which was reduced by mTORC1 inhibition with rapamycin in vivo . Remarkably, in vivo administration of a pan‐cathepsin inhibitor restored LT β R expression, LT α 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.