PMID- 34718162 OWN - NLM STAT- MEDLINE DCOM- 20211214 LR - 20221221 IS - 1873-0183 (Electronic) IS - 1568-9972 (Print) IS - 1568-9972 (Linking) VI - 20 IP - 12 DP - 2021 Dec TI - Therapeutic mTOR blockade in systemic autoimmunity: Implications for antiviral immunity and extension of lifespan. PG - 102984 LID - S1568-9972(21)00264-0 [pii] LID - 10.1016/j.autrev.2021.102984 [doi] AB - The mechanistic target of rapamycin (mTOR) pathway integrates metabolic cues into cell fate decisions. A particularly fateful event during the adaptive immune response is the engagement of a T cell receptor by its cognate antigen presented by an antigen-presenting cell (APC). Here, the induction of adequate T cell activation and lineage specification is critical to mount protective immunity; at the same time, inadequate activation, which could lead to autoimmunity, must be avoided. mTOR forms highly conserved protein complexes 1 and 2 that shape lineage specification by integrating signals originating from TCR engagement, co-stimulatory or co-inhibitory receptors and cytokines and availability of nutrients. If one considers autoimmunity as the result of aberrant lineage specification in response to such signals, the importance of this pathway becomes evident; this provides the conceptual basis for mTOR inhibition in the treatment of systemic autoimmunity, such as systemic lupus erythematosus (SLE). Clinical trials in SLE patients have provided preliminary evidence that mTOR blockade by sirolimus (rapamycin) can reverse pro-inflammatory lineage skewing, including the expansion of Th17 and double-negative T cells and plasma cells and the contraction of regulatory T cells. Moreover, sirolimus has shown promising efficacy in the treatment of refractory idiopathic multicentric Castleman disease, newly characterized by systemic autoimmunity due to mTOR overactivation. Alternatively, mTOR blockade enhances responsiveness to vaccination and reduces infections by influenza virus in healthy elderly subjects. Such seemingly contradictory findings highlight the importance to further evaluate the clinical effects of mTOR manipulation, including its potential role in treatment of COVID-19 infection. mTOR blockade may extend healthy lifespan by abrogating inflammation induced by viral infections and autoimmunity. This review provides a mechanistic assessment of mTOR pathway activation in lineage specification within the adaptive and innate immune systems and its role in health and autoimmunity. We then discuss some of the recent experimental and clinical discoveries implicating mTOR in viral pathogensis and aging. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Geier, Christian AU - Geier C AD - Division of Rheumatology, Department of Medicine, College of Medicine, State University of New York, Syracuse, NY, USA. FAU - Perl, Andras AU - Perl A AD - Division of Rheumatology, Department of Medicine, College of Medicine, State University of New York, Syracuse, NY, USA; Department of Microbiology and Immunology, College of Medicine, State University of New York, Syracuse, NY, USA; Department of Biochemistry and Molecular Biology, College of Medicine, State University of New York, Syracuse, NY, USA. Electronic address: perla@upstate.edu. LA - eng GR - R01 AI072648/AI/NIAID NIH HHS/United States GR - R01 AI122176/AI/NIAID NIH HHS/United States GR - R34 AI141304/AI/NIAID NIH HHS/United States GR - U01 AR076092/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Review DEP - 20211027 PL - Netherlands TA - Autoimmun Rev JT - Autoimmunity reviews JID - 101128967 RN - 0 (Antiviral Agents) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Aged MH - Antiviral Agents/therapeutic use MH - Autoimmunity MH - *COVID-19 MH - Humans MH - Longevity MH - *Lupus Erythematosus, Systemic/drug therapy MH - SARS-CoV-2 MH - TOR Serine-Threonine Kinases/therapeutic use PMC - PMC8550885 OTO - NOTNLM OT - Antiviral immunity OT - Autoimmunity OT - Immune cell lineage specification OT - Lifespan extension; OT - Mechanistic target of rapamycin OT - Sirolimus OT - Systemic lupus erythematosus OT - mTOR EDAT- 2021/11/01 06:00 MHDA- 2021/12/15 06:00 PMCR- 2021/10/27 CRDT- 2021/10/31 20:50 PHST- 2021/08/12 00:00 [received] PHST- 2021/08/20 00:00 [accepted] PHST- 2021/11/01 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/10/31 20:50 [entrez] PHST- 2021/10/27 00:00 [pmc-release] AID - S1568-9972(21)00264-0 [pii] AID - 102984 [pii] AID - 10.1016/j.autrev.2021.102984 [doi] PST - ppublish SO - Autoimmun Rev. 2021 Dec;20(12):102984. doi: 10.1016/j.autrev.2021.102984. Epub 2021 Oct 27.