{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:07:43Z","timestamp":1768514863965,"version":"3.49.0"},"posted":{"date-parts":[[2024,8,4]]},"group-title":"Immunology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,4]],"date-time":"2024-08-04T00:00:00Z","timestamp":1722729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>\n                    We aim to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in systemic lupus erythematosus (SLE) development, the in\n                    <jats:italic>vivo<\/jats:italic>\n                    regulation of mTORC2 by type I interferon (IFN) signaling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an\n                    <jats:italic>in vivo<\/jats:italic>\n                    lupus mouse model and an\n                    <jats:italic>in vitro<\/jats:italic>\n                    coculture model using human PBMCs.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Method<\/jats:title>\n                  <jats:p>\n                    We first induced lupus-like disease in T cell specific\n                    <jats:italic>Rictor<\/jats:italic>\n                    , a key component of mTORC2, deficient mice by topical application of imiquimod (IMQ) and monitored disease development. Next, we investigated the changes of mTORC2 signaling and immunological phenotypes in type I IFNAR deficient Lpr mice. We then tested the beneficial effects of anti-\n                    <jats:italic>Rictor<\/jats:italic>\n                    antisense oligonucleotide (\n                    <jats:italic>Rictor<\/jats:italic>\n                    -ASO) in a mouse model of lupus: MRL\/\n                    <jats:italic>lpr<\/jats:italic>\n                    mice. Finally, we examined the beneficial effects of\n                    <jats:italic>RICTOR<\/jats:italic>\n                    -ASO on SLE patients\u2019 PBMCs using an\n                    <jats:italic>in vitro<\/jats:italic>\n                    T-B cell coculture assay.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    T cell specific\n                    <jats:italic>Rictor<\/jats:italic>\n                    deficient mice have reduced age-associated B cells, plasma cells and germinal center B cells, and less autoantibody production than WT mice following IMQ treatment. IFNAR1 deficient Lpr mice have reduced mTORC2 activity in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells accompanied by restored CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell glucose metabolism, partially recovered T cell trafficking, and reduced systemic inflammation.\n                    <jats:italic>In vivo Rictor<\/jats:italic>\n                    -ASO treatment improves renal function and pathology in MRL\/\n                    <jats:italic>lpr<\/jats:italic>\n                    mice, along with improved immunopathology. In human SLE (N = 5) PBMCs derived T-B coculture assay,\n                    <jats:italic>RICTOR-<\/jats:italic>\n                    ASO significantly reduce immunoglobulin and autoantibodies production (P &lt; 0.05).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Targeting mTORC2 could be a promising therapeutic for SLE.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.08.01.606069","type":"posted-content","created":{"date-parts":[[2024,8,4]],"date-time":"2024-08-04T12:55:13Z","timestamp":1722776113000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting mechanistic target of rapamycin complex 2 attenuates immunopathology in Systemic Lupus Erythematosus"],"prefix":"10.64898","author":[{"given":"Minji","family":"Ai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xian","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Carrer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paymaan","family":"Jafar-nejad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanfeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Gades D.V.M.","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9072-9871","authenticated-orcid":false,"given":"Mariam","family":"Alexander","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario A.","family":"Bautista","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali A.","family":"Duarte Garcia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9909-7732","authenticated-orcid":false,"given":"Hu","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024080607451125000_2024.08.01.606069v1.1","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2022-223035"},{"key":"2024080607451125000_2024.08.01.606069v1.2","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1001\/jama.2024.2315","article-title":"Systemic Lupus Erythematosus","volume":"331","year":"2024","journal-title":"JAMA"},{"key":"2024080607451125000_2024.08.01.606069v1.3","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/rai2.12045","article-title":"Azathioprine-induced pancytopenia: A case report","volume":"2","year":"2022","journal-title":"Rheumatol Autoimmun"},{"key":"2024080607451125000_2024.08.01.606069v1.4","doi-asserted-by":"crossref","unstructured":"Kirou KA , Dall\u2018Era M , Aranow C , et al. 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