Evolving Perspectives of mTOR Complexes in Immunity and Transplantation
2015; Elsevier BV; Volume: 15; Issue: 4 Linguagem: Inglês
10.1111/ajt.13151
ISSN1600-6143
AutoresDaniel Fantus, Angus W. Thomson,
Tópico(s)Receptor Mechanisms and Signaling
ResumoSince the discovery of Rapamycin (RAPA) and its immunosuppressive properties, enormous progress has been made in characterizing the mechanistic target of rapamycin (mTOR). Use of RAPA and its analogues (rapalogs) as anti-rejection agents has been accompanied by extensive investigation of how targeting of mTOR complex 1 (mTORC1), the principal target of RAPA, and more recently mTORC2, affects the function of immune cells, as well as vascular endothelial cells, that play crucial roles in regulation of allograft rejection. While considerable knowledge has accumulated on the function of mTORC1 and 2 in T cells, understanding of the differential roles of these complexes in antigen-presenting cells, NK cells and B cells/plasma cells is only beginning to emerge. Immune cell-specific targeting of mTORC1 or mTORC2, together with use of novel, second generation, dual mTORC kinase inhibitors (TORKinibs) have started to play an important role in elucidating the roles of these complexes and their potential for targeting in transplantation. Much remains unknown about the role of mTOR complexes and the consequences of mTOR targeting on immune reactivity in clinical transplantation. Here we address recent advances in understanding and evolving perspectives of the role of mTOR complexes and mTOR targeting in immunity, with extrapolation to transplantation. Since the discovery of Rapamycin (RAPA) and its immunosuppressive properties, enormous progress has been made in characterizing the mechanistic target of rapamycin (mTOR). Use of RAPA and its analogues (rapalogs) as anti-rejection agents has been accompanied by extensive investigation of how targeting of mTOR complex 1 (mTORC1), the principal target of RAPA, and more recently mTORC2, affects the function of immune cells, as well as vascular endothelial cells, that play crucial roles in regulation of allograft rejection. While considerable knowledge has accumulated on the function of mTORC1 and 2 in T cells, understanding of the differential roles of these complexes in antigen-presenting cells, NK cells and B cells/plasma cells is only beginning to emerge. Immune cell-specific targeting of mTORC1 or mTORC2, together with use of novel, second generation, dual mTORC kinase inhibitors (TORKinibs) have started to play an important role in elucidating the roles of these complexes and their potential for targeting in transplantation. Much remains unknown about the role of mTOR complexes and the consequences of mTOR targeting on immune reactivity in clinical transplantation. Here we address recent advances in understanding and evolving perspectives of the role of mTOR complexes and mTOR targeting in immunity, with extrapolation to transplantation. Since the discovery of Rapamycin (RAPA) (1.Vezina C Kudelski A Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle.J Antibiot (Tokyo). 1975; 28: 721-726Crossref PubMed Scopus (1302) Google Scholar), much progress has been made in characterizing the mechanistic target of rapamycin (mTOR) signaling network, including its roles in mRNA translation and other cell growth-related responses. The immunosuppressive and anti-proliferative properties of RAPA (2.Heitman J Movva NR Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast.Science. 1991; 253: 905-909Crossref PubMed Scopus (1551) Google Scholar,3.Schmelzle T Hall MN. TOR, a central controller of cell growth.Cell. 2000; 103: 253-262Abstract Full Text Full Text PDF PubMed Scopus (1729) Google Scholar) are mediated indirectly, via allosteric interaction with the intracellular immunophilin, FK506-binding protein 12 (FKBP12), that binds to the FKBP12-RAPA-binding (FRB) domain of mTOR (Figure 1). mTOR encodes a 289-kDa serine/threonine kinase and contains a C-terminal region with strong homology to the catalytic domain of phosphatidylinositol 3-kinase (PI3K) and phosphatidylinositol 4-kinase (Figure 1). The large size of mTOR, coupled with its numerous domains, allows it to function as an intracellular scaffold and signaling node. As understanding of mTOR structure and biochemistry advanced, RAPA was introduced as kidney transplant rejection therapy in 1999 (4.Groth CG Backman L Morales JM Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group.Transplantation. 1999; 67 (et al): 1036-1042Crossref PubMed Scopus (858) Google Scholar). Its clinical utility later expanded to include chemotherapy of advanced renal cell carcinoma, prevention of restenosis of drug-eluting stents following angioplasty and as an orphan drug for tuberous sclerosis and uveitis. In recent years, novel, next-generation mTOR inhibitors that work through an adenosine triphosphate (ATP)-competitive mechanism, or that inhibit both mTOR and PI3K, have been developed (5.Wander SA Hennessy BT Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: How pathway complexity informs therapeutic strategy.J Clin Invest. 2011; 121: 1231-1241Crossref PubMed Scopus (347) Google Scholar,6.Bhagwat SV Crew AP. Novel inhibitors of mTORC1 and mTORC2.Curr Opin Investig Drugs. 2010; 11: 638-645PubMed Google Scholar). Unlike RAPA, these agents bind directly to the C-terminal catalytic domain of mTOR and, consequently, inhibit kinase activity directly. They are undergoing clinical testing in malignant disease, including advanced breast and renal cancers. RAPA has achieved mixed results in renal transplantation. Side effects, including nephrotoxicity, dyslipidemia, impaired wound healing and leucopenia, have led to high discontinuation rates (7.Ekberg H Tedesco-Silva H Demirbas A Reduced exposure to calcineurin inhibitors in renal transplantation.N Engl J Med. 2007; 357 (et al): 2562-2575Crossref PubMed Scopus (1442) Google Scholar,8.Tedesco Silva Jr, H Cibrik D Johnston T Everolimus plus reduced-exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients.Am J Transplant. 2010; 10 (et al): 1401-1413Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). Thus, in the ELITE-Symphony study, serious adverse events occurred in >50% of patients in the low-dose RAPA (sirolimus) group. The occurrence of rare, paradoxical inflammatory disorders, such as pneumonitis and glomerulonephritis (9.Sanchez-Fructuoso AI Ruiz JC Perez-Flores I Gomez Alamillo C Calvo Romero N Arias M. Comparative analysis of adverse events requiring suspension of mTOR inhibitors: Everolimus versus sirolimus.Transplant Proc. 2010; 42: 3050-3052Crossref PubMed Scopus (46) Google Scholar,10.Errasti P Izquierdo D Martin P Pneumonitis associated with mammalian target of rapamycin inhibitors in renal transplant recipients: a single-center experience.Transplant Proc. 2010; 42 (et al): 3053-3054Crossref PubMed Scopus (31) Google Scholar), together with evidence that mTOR inhibition can augment anti-viral immunity (11.Amiel E Everts B Freitas TC Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice.J Immunol. 2012; 189 (et al): 2151-2158Crossref PubMed Scopus (128) Google Scholar), have prompted intensive investigation of the impact of mTOR inhibition on innate and adaptive immunity. This has resulted in key advances over the past 5 years that have modified perception of mTOR inhibition as an immunosuppressive modality and identified new and diverse regulatory properties of mTOR in innate and adaptive immune cells. They have also shed light on how mTOR modulates immunity through metabolic programming. Here, we highlight these advances and offer insight into how this new knowledge may improve understanding of the role of mTOR in experimental and clinical transplantation (Table 1).Table 1The multifaceted roles of mTOR complexes in immune cell populations and their putative roles in clinical organ transplantationCell typeRole of mTORPutative role of mTOR in clinical transplantationcDCPromotes growth, proliferation, maturation, alters pro/anti-inflammatory cytokine secretion (27.Turnquist H Raimondi G Zahorchak AF Fischer RT Wang Z Thomson AW. Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance.J Immunol. 2007; 178: 7018-7031Crossref PubMed Scopus (353) Google Scholar,30.Ohtani M Nagai S Kondo S Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells.Blood. 2008; 112 (et al): 635-643Crossref PubMed Scopus (217) Google Scholar,31.Turnquist HR Cardinal J Macedo C MTOR and GSK-3 shape the CD4+ T cell stimulatory and differentiation capacity of myeloid DC following exposure to LPS.Blood. 2010; 115 (et al): 4758-4769Crossref PubMed Scopus (92) Google Scholar) suppresses inflammation (mTORC2) (38.Brown J Wang H Suttles J Graves DT Martin M. Mammalian target of rapamycin complex 2 (mTORC2) negatively regulates Toll-like receptor 4-mediated inflammatory response via FoxO1.J Biol Chem. 2011; 286: 44295-44305Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar,39.Raich-Regue D Rosborough BR Turnquist HR Thomson AW. Myeloid dendritic cell-specific mTORC2 deficiency enhances alloreactive Th1 and Th17 cell responses and skin graft rejection.Am J Transplant. 2014; 14 (Suppl 3, Abstract #584): 18Crossref Google Scholar) and restrains T cell responses in human myeloid DC (mTORC1) (32.Weichhart T Costantino G Poglitsch M The TSC-mTOR signaling pathway regulates the innate inflammatory response.Immunity. 2008; 29 (et al): 565-577Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar,33.Haidinger M Poglitsch M Geyeregger R A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation.J Immunol. 2010; 185 (et al): 3919-3931Crossref PubMed Scopus (174) Google Scholar)May either promote (e.g. rejection: ACR) or restrain (e.g. pneumonitis) immune hyper-responsivenesspDCPromotes activation (TLR9), type-I IFN production and restrains (TLR7) Tmem and Treg proliferation (43.Cao W Manicassamy S Tang H Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway.Nat Immunol. 2008; 9 (et al): 1157-1164Crossref PubMed Scopus (315) Google Scholar,44.Boor PP Metselaar HJ Mancham S van der Laan LJ Kwekkeboom J. Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions.Clin Exp Immunol. 2013; 174: 389-401Crossref PubMed Scopus (29) Google Scholar)May regulate function including interaction with TregEffector T cellsDrives Th1 (mTORC1), Th2 (mTORC2+/− mTORC1), and Th17 (mTORC1) cell differentiation and growth (48.Delgoffe GM Pollizzi KN Waickman AT The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2.Nat Immunol. 2011; 12 (et al): 295-303Crossref PubMed Scopus (832) Google Scholar,49.Delgoffe GM Kole TP Zheng Y The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment.Immunity. 2009; 30 (et al): 832-844Abstract Full Text Full Text PDF PubMed Scopus (916) Google Scholar,52.Lee K Gudapati P Dragovic S Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways.Immunity. 2010; 32 (et al): 743-753Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar)Promotes expansion with role in rejection (ACR, AMR, CAMR)CD8 memory T cellsRestrains anti-viral and anti-tumor immunity (56.Araki K Turner AP Shaffer VO MTOR regulates memory CD8 T-cell differentiation.Nature. 2009; 460 (et al): 108-112Crossref PubMed Scopus (1156) Google Scholar, 57.Berezhnoy A Castro I Levay A Malek TR Gilboa E. Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity.J Clin Invest. 2014; 124: 188-197Crossref PubMed Scopus (109) Google Scholar, 58.Ferrer IR Wagener ME Robertson JM Turner AP Araki K Ahmed R Cutting edge: Rapamycin augments pathogen-specific but not graft-reactive CD8+ T cell responses.J Immunol. 2010; 185 (et al): 2004-2008Crossref PubMed Scopus (93) Google Scholar)May promote viral infections, including CMV, human herpesvirus 8 and BK virus (96.Liacini A Seamone ME Muruve DA Tibbles LA. Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: Toward a new therapy for BK virus infection.Transplantation. 2010; 90: 1450-1457Crossref PubMed Scopus (113) Google Scholar,97.Nashan B Gaston R Emery V Review of cytomegalovirus infection findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in de novo renal transplant recipients.Transplantation. 2012; 93 (et al): 1075-1085Crossref PubMed Scopus (109) Google Scholar)TregPromotes homeostasis and function (mTORC1) (65.Zeng H Yang K Cloer C Neale G Vogel P Chi H. MTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function.Nature. 2013; 499: 485-490Crossref PubMed Scopus (550) Google Scholar) and limits expansion (mTORC1+/− mTORC2) (50.Battaglia M Stabilini A Roncarolo MG. Rapamycin selectively expands CD4 + CD25 + FoxP3+ regulatory T cells.Blood. 2005; 105: 4743-4748Crossref PubMed Scopus (955) Google Scholar)May restrict role in promotion of toleranceNeutrophilsFormation of neutrophil extracellular traps (NETs) (66.McInturff AM Cody MJ Elliott EA Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 alpha.Blood. 2012; 120 (et al): 3118-3125Crossref PubMed Scopus (182) Google Scholar), promotes chemotaxis (mTORC2) (67.He Y Li D Cook SL Mammalian target of rapamycin and Rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and the actin cytoskeleton.Mol Biol Cell. 2013; 24 (et al): 3369-3380Crossref PubMed Scopus (63) Google Scholar,68.Liu L Gritz D Parent CA. PKCbetaII acts downstream of chemoattractant receptors and mTORC2 to regulate cAMP production and myosin II activity in neutrophils.Mol Biol Cell. 2014; 25: 1446-1457Crossref PubMed Google Scholar)May promote role in rejection (ACR, AMR, CAMR)NK cellsPromotes development in the BM, activation in the periphery and IL-15-induced function (71.Marcais A Cherfils-Vicini J Viant C The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells.Nat Immunol. 2014; 15 (et al): 749-757Crossref PubMed Scopus (370) Google Scholar)May promote role in rejection (ACR, AMR, CAMR)B cellsPromotes growth, proliferation, maturation, antibody class switching and production (mTORC1+mTORC2) (74.Zhang S Readinger JA DuBois W Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production.Blood. 2011; 117 (et al): 1228-1238Crossref PubMed Scopus (102) Google Scholar,76.Lee K Heffington L Jellusova J Requirement for Rictor in homeostasis and function of mature B lymphoid cells.Blood. 2013; 122 (et al): 2369-2379Crossref PubMed Scopus (55) Google Scholar, 77.Zhang Y Hu T Hua C Rictor is required for early B cell development in bone marrow.PLoS One. 2014; 9 (et al): e103970Crossref PubMed Scopus (24) Google Scholar, 78.Keating R Hertz T Wehenkel M The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus.Nat Immunol. 2013; 14 (et al): 1266-1276Crossref PubMed Scopus (145) Google Scholar) but decreases IL-7 receptor and RAG recombinase gene expression (mTORC2) (98.Lazorchak AS Liu D Facchinetti V Sin1-mTORC2 suppresses rag and il7r gene expression through Akt2 in B cells.Mol Cell. 2010; 39 (et al): 433-443Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar)May promote role in rejection (ACR, AMR, CAMR)Plasma cellsUnknownAlloantibody generation in AMR/CAMREndothelial cellsPromotes growth, proliferation, maturation, alters pro/anti-inflammatory cytokine secretion, negatively regulates Treg expansion and increases VCAM-1 expression (mTORC2) (82.Wang C Yi T Qin L Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells.J Clin Invest. 2013; 123 (et al): 1677-1693Crossref PubMed Scopus (57) Google Scholar,83.Wang C Qin L Manes TD Kirkiles-Smith NC Tellides G Pober JS. Rapamycin antagonizes TNF induction of VCAM-1 on endothelial cells by inhibiting mTORC2.J Exp Med. 2014; 211: 395-404Crossref PubMed Scopus (61) Google Scholar)May promote role in rejection (ACR, AMR, CAMR)ACR: acute cell-mediated rejection; AMR: antibody-mediated rejection; CAMR: chronic antibody-mediated rejection; cDC: conventional dendritic cell; IFN: interferon; pDC: plasmacytoid DC; RAPA: Rapamycin; TLR: Toll-like receptor; Treg: regulatory T cell; VCAM-1: vascular cell adhesion molecule-1; CMV: cytomegalovirus. Open table in a new tab ACR: acute cell-mediated rejection; AMR: antibody-mediated rejection; CAMR: chronic antibody-mediated rejection; cDC: conventional dendritic cell; IFN: interferon; pDC: plasmacytoid DC; RAPA: Rapamycin; TLR: Toll-like receptor; Treg: regulatory T cell; VCAM-1: vascular cell adhesion molecule-1; CMV: cytomegalovirus. mTOR is an evolutionarily-conserved serine-threonine kinase that operates in at least two distinct, multi-protein complexes (Figure 1). Its signaling role in immune cells has been described extensively in previous reviews (12.Thomson AW Turnquist HR Raimondi G. Immunoregulatory functions of mTOR inhibition.Nat Rev Immunol. 2009; 9: 324-337Crossref PubMed Scopus (669) Google Scholar, 13.Limon JJ Fruman DA. Akt and mTOR in B cell activation and differentiation.Front Immunol. 2012; 3: 228Crossref PubMed Scopus (149) Google Scholar, 14.Powell JD Pollizzi KN Heikamp EB Horton MR. Regulation of immune responses by mTOR.Annu Rev Immunol. 2012; 30: 39-68Crossref PubMed Scopus (582) Google Scholar, 15.Chi H. Regulation and function of mTOR signalling in T cell fate decisions.Nat Rev Immunol. 2012; 12: 325-338Crossref PubMed Scopus (621) Google Scholar, 16.Shimobayashi M Hall MN. Making new contacts: The mTOR network in metabolism and signalling crosstalk.Nat Rev Mol Cell Biol. 2014; 15: 155-162Crossref PubMed Scopus (789) Google Scholar) mTORC1 is regulated by environmental cues (nutrients, growth factors and energy) and drives cell growth and anabolism. Metabolic processes regulated by mTORC1 include protein, lipid and mitochondrial biosynthesis and autophagy (Figure 1). Other than regulation of mTORC1 via growth factor signaling through PI3K, amino acids directly modulate mTORC1 in a PI3K-independent fashion (17.Groenewoud MJ Zwartkruis FJ. Rheb and Rags come together at the lysosome to activate mTORC1.Biochem Soc Trans. 2013; 41: 951-955Crossref PubMed Scopus (58) Google Scholar,18.Sancak Y Peterson TR Shaul YD The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.Science. 2008; 320 (et al): 1496-1501Crossref PubMed Scopus (1944) Google Scholar). Critical proteins include a group of four recombinase-activating gene (Rag) guanosine-5′-triphosphate (GTP) ases that form heterodimers and recruit mTORC1 to lysosomes when in their GTP-bound form. Recruitment to the lysosome places mTORC1 in proximity to Ras homolog enriched in brain (Rheb). Interaction of Rheb with the kinase domain of mTOR results in either enhanced catalytic activity of mTOR or an increase in substrate turnover. The past 5 years have seen major advances in our understanding of mTORC2. Distinct substrates include serine 473 within the hydrophobic motif of Akt, as well as several members of the cAMP-dependent protein kinase A, cyclic GMP-dependent protein kinase G and phospholipid-dependent protein kinase C (AGC) kinase family, including protein kinase C (PKC) and the serum and glucocorticoid-induced kinase-1 (SGK-1) (Figure 1). Zinzalla et al (19.Zinzalla V Stracka D Oppliger W Hall MN. Activation of mTORC2 by association with the ribosome.Cell. 2011; 144: 757-768Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar) demonstrated that the ribosome interacts physically with and activates mTORC2 in mammalian cells, establishing a novel mechanism linking mTOR complexes and protein synthesis. Experiments in yeast and mammalian cells indicate a role for mTORC2 in regulation of the actin cytoskeleton (20.Sarbassov DD Ali SM Kim DH Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton.Curr Biol. 2004; 14 (et al): 1296-1302Abstract Full Text Full Text PDF PubMed Scopus (2157) Google Scholar,21.Jacinto E Loewith R Schmidt A Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive.Nat Cell Biol. 2004; 6 (et al): 1122-1128Crossref PubMed Scopus (1687) Google Scholar), though as yet, this has not been substantiated in immune cells. Meanwhile, germline and tissue-specific deletion of the essential mTORC2 component Rictor has shed light on the physiologic function of mTORC2 (22.Oh WJ Jacinto E. MTOR complex 2 signaling and functions.Cell Cycle. 2011; 10: 2305-2316Crossref PubMed Scopus (410) Google Scholar). Thus, whereas germline deletion of Rictor in mice is embryonic lethal, its deletion in kidney, muscle and adipose tissue produces only minor phenotypes. Interestingly, deletion of Rictor in brain or Purkinje cells affects neuron size, morphology and function (23.Thomanetz V Angliker N Cloetta D Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology.J Cell Biol. 2013; 201 (et al): 293-308Crossref PubMed Scopus (172) Google Scholar). The prevailing view is that mTOR links nutritional availability with metabolism by coordinating processes that facilitate cell growth. Rapid expansion of lymphocytes during immune responses is achieved largely through an mTOR-mediated program of nutrient uptake and oxidative glycolysis that generates ATP and provides substrates for increasing biomass. Recently, the mechanism of "trained immunity" (which refers to the memory characteristics of the innate immune system that protect against secondary infections after certain exposures) in monocytes has been explained by a metabolic shift towards aerobic glycolysis through the mTOR pathway (24.Cheng SC Quintin J Cramer RA MTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity.Science. 2014; 345 (et al): 1250684Crossref PubMed Scopus (1060) Google Scholar). As outlined below, other immune cells (neutrophils, dendritic cells [DC], memory T cells [Tmem] and regulatory T cells [Treg]) engage mTOR differently, due to markedly different metabolic requirements. In contrast, autophagy is a catabolic process that degrades a range of substrates including proteins, organelles and microorganisms and promotes cell survival in most circumstances. mTORC1 is a major inhibitor of this pathway via phosphorylation and sequestration of key protein drivers of autophagy (e.g. Unc-51 like kinase-1) (25.Wong PM Puente C Ganley IG Jiang X. The ULK1 complex: Sensing nutrient signals for autophagy activation.Autophagy. 2013; 9: 124-137Crossref PubMed Scopus (345) Google Scholar). With the acquisition of new knowledge linking autophagy to both ischemia–reperfusion injury and innate and adaptive immunity, understanding how autophagy impacts transplantation and graft survival is an exciting new area of investigation. This topic has been reviewed recently (26.Bizargity P Schroppel B. Autophagy: Basic principles and relevance to transplant immunity.Am J Transplant. 2014; 14: 1731-1739Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). In addition, improved understanding of the relationship between mTOR inhibitors and autophagy is clearly warranted. Much of our understanding of how mTOR regulates conventional DC (cDC) function stems from studies of their response to RAPA. Timing and duration of exposure to RAPA, extent of mTOR inhibition, DC activation status and the nature of the stimulus at the time of exposure to RAPA have emerged as important variables. Protracted mTORC1 inhibition with RAPA inhibits DC maturation and their ability to induce effector T cell proliferation, while at the same time promoting Treg (27.Turnquist H Raimondi G Zahorchak AF Fischer RT Wang Z Thomson AW. Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance.J Immunol. 2007; 178: 7018-7031Crossref PubMed Scopus (353) Google Scholar,28.Hackstein H Taner T Zahorchak AF Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo.Blood. 2003; 101 (et al): 4457-4463Crossref PubMed Scopus (327) Google Scholar), thus conferring "tolerogenic" properties on these RAPA-conditioned DC (RAPA-DC) (12.Thomson AW Turnquist HR Raimondi G. Immunoregulatory functions of mTOR inhibition.Nat Rev Immunol. 2009; 9: 324-337Crossref PubMed Scopus (669) Google Scholar,29.Macedo C Turquist H Metes D Thomson AW. Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation.Transplant Res. 2012; 1: 16Crossref PubMed Scopus (39) Google Scholar). Paradoxically, Ohtani et al (30.Ohtani M Nagai S Kondo S Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells.Blood. 2008; 112 (et al): 635-643Crossref PubMed Scopus (217) Google Scholar) and Turnquist et al (31.Turnquist HR Cardinal J Macedo C MTOR and GSK-3 shape the CD4+ T cell stimulatory and differentiation capacity of myeloid DC following exposure to LPS.Blood. 2010; 115 (et al): 4758-4769Crossref PubMed Scopus (92) Google Scholar) identified enhanced IL-12p40/p70 production by lipopolysaccharide (LPS)-stimulated, RAPA-exposed mouse bone marrow DC (BMDC). It appeared that mTOR could regulate IL-12 expression through an autocrine action of IL-10. Consistent with the above, Weichhart et al showed (32.Weichhart T Costantino G Poglitsch M The TSC-mTOR signaling pathway regulates the innate inflammatory response.Immunity. 2008; 29 (et al): 565-577Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar) that human LPS-stimulated, RAPA-treated monocytes/DC had enhanced IL-12, but blocked IL-10 production (via regulation of NFKβ and signal transducer and activator of transcription 3 (STAT3) signaling). In a follow-up study, the same group (33.Haidinger M Poglitsch M Geyeregger R A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation.J Immunol. 2010; 185 (et al): 3919-3931Crossref PubMed Scopus (174) Google Scholar) observed that inhibition of mTORC1 in DC with RAPA gave divergent results, depending on the DC type investigated (isolated blood myeloid DC [mDC] versus monocyte-derived DC [moDC] generated in vitro). In mDC treated with RAPA and stimulated with LPS (or CD40L), NFKβ and IL-12 production increased and T cell activation was enhanced, whereas in similarly stimulated cultured moDC, NFKβ and IL-12 were diminished and T cell activation impaired. The authors attributed these important differences to a constitutively active basal mTOR pathway in moDC required to maintain cell growth and homeostasis. Extending these studies, Weichart et al (34.Weichhart T Haidinger M Katholnig K Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells.Blood. 2011; 117 (et al): 4273-4283Crossref PubMed Scopus (103) Google Scholar) found that, in the presence of RAPA, the anti-inflammatory potency of glucocorticoids on human mDC was reduced. These studies may help explain glucocorticoid resistance to RAPA-induced pulmonary pneumonitis in the clinic. Ohtani et al (35.Ohtani M Hoshii T Fujii H Koyasu S Hirao A Matsuda S. Cutting edge: mTORC1 in intestinal CD11c+ CD11b+ dendritic cells regulates intestinal homeostasis by promoting IL-10 production.J Immunol. 2012; 188: 4736-4740Crossref PubMed Scopus (63) Google Scholar) have subsequently described suppressed IL-10 levels, but enhanced CD86 expression by intestinal mTORC1-deficient CD11c+CD11b+ DC, consistent with increased susceptibility to sodium sulfate-induced colitis. The immunostimulatory effects of RAPA on DC function have also been investigated in the context of therapeutic vaccination. Brief exposure of DC to a combination of RAPA and toll-like receptor (TLR) agonists in vitro led to both improved generation of Ag-specific CD8+ T cells in vivo and anti-tumor immunity (11.Amiel E Everts B Freitas TC Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice.J Immunol. 2012; 189 (et al): 2151-2158Crossref PubMed Scopus (128) Google Scholar). Furthermore, this novel approach extended DC lifespan and prolonged DC activation. In a separate study (36.Jagannath C Bakhru P. Rapamycin-induced enhancement of vaccine efficacy in mice.Methods Mol Biol. 2012; 821: 295-303Crossref PubMed Scopus (37) Google Scholar), co-administration of RAPA together with BCG vaccine, enhanced Th1 immunity. Whether these effects are mediated by mTORC1, mTORC2 or both complexes will require genetic targeting experiments. Like mTOR inhibition, mTOR augmentation in DC can disturb their homeostasis. Thus, in a recent study (37.Pan H O'Brien TF Wright G Critical role of the tumor suppressor tuberous sclerosis complex 1 in dendritic cell activation of CD4 T cells by promoting MHC class II expression via IRF4 and C
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