autophagy is induced downstream of signaling by  danger  receptors including toll like receptors ( tlr ; xu et al .
, 2007 ; delgado et al . , 2008 ) , retinoic acid inducible gene i - like receptors ( rlr ; yano et al . , 2008 ; cooney et al . , 2010 ; travassos et al . ,
 xenophagy  describes the process by which intracellular microbes are selectively degraded by autophagy ( levine , 2005 ) .
xenophagy eliminates bacteria that access the cytosol including streptococcus pyogenes ( nakagawa et al . , 2004 ) and mycobacterium tuberculosis ( gutierrez et al . ,
guerin ( bcg ) , autophagy facilitates the fusion of mycobacteria containing vacuoles with late endosomes / lysosomes to promote mycobacteria degradation ( singh et al . , 2006 ) .
salmonella - containing vacuoles are targeted by lc3 ( birmingham et al . , 2006 ) and can be engulfed by autophagosomes ( kageyama et al . , 2011 ) .
interestingly , recruitment of autophagy machinery to damaged bacterial vacuoles involves the exposure of host sugar residues that attract receptor galectin 8 ( thurston et al . , 2012 ) .
one example is the degradation of the sindbis virus capsid by the autophagy pathway ( orvedahl et al . , 2010 ) .
autophagy can also impair viral replication by trafficking cytosolic viral replication products to the endolysosomal compartment where they are detected by tlr and a type i interferon ( ifn ) response is triggered .
this is the case for vesicular stomatitis virus ( vsv ) infection of plasmacytoid dendritic cells ( pdc ; lee et al . , 2007 ) .
given its role in anti - viral defense , many viruses encode proteins to disable autophagy .
gammaherpes virus 68 ( ku et al . , 2008 ) , influenza a virus ( gannage et al . , 2009 ) ,
herpes simplex virus-1 ( hsv-1 ; orvedahl et al . , 2007 ) , human cytomegalovirus ( chaumorcel et al . ,
2012 ) , and human immunodeficiency virus ( hiv;kyei et al . , 2009 ) are examples of viruses that encode proteins to block autophagy initiation by interfering with beclin 1 activity
. other interesting examples of viral interference with the autophagy pathway include kaposi s sarcoma - associated herpesvirus encoded fadd - like interleukin-1 beta - converting enzyme ( flice)-like inhibitor protein that blocks interaction between lc3 and atg4 ( lee et al . , 2009 ) and
hiv nef that prevents autophagosomal maturation ( kyei et al . , 2009 ) . like viruses
l. monocytogenes , via the expression of acta , recruits host proteins to its surface to disguise itself from autophagic recognition ( yoshikawa et al . , 2009 )
similarly , shigella hides from the autophagy machinery by expressing icsb , that inhibits atg5 binding to the shigella surface ( ogawa et al . ,
this is particularly well described for interleukin ( il)-1 and il-18 , where the absence of autophagy exacerbates their secretion by murine macrophages when stimulated with pro - inflammatory compounds .
specifically , this has been described for beclin1 ( nakahira et al . , 2011 ) ,
lc3b ( nakahira et al . , 2011 ) , atg16l1 ( saitoh et al . , 2008 ) , and atg7 ( saitoh et al . , 2008 ) macrophages or following expression of inactive atg4b or due to treatment with the chemical autophagy inhibitor 3-methyladenine ( 3-ma ; saitoh et al . , 2008 ; harris et al . , 2011
) . enhanced secretion of il-1 also occurs when human peripheral blood mononuclear cells are stimulated in the presence of an impaired autophagy pathway due to treatment with 3-ma ( crisan et al . ,
conversely , stimulation of murine dc with rapamycin suppresses il-1 production in response to inflammatory stimuli ( harris et al . , 2011 ) .
rapamycin administration in vivo , inhibits the detected increase in il-1 but not il-12 , in the serum 4  h following lipopolysaccharide ( lps ) treatment ( harris et al . , 2011 ) .
stimuli that do include lps , or treatment of lps - primed macrophages with adenosine 5-triphosphate ( atp ) or monosodium urate ( msu ) .
salmonella typhimurium or muramyl dipeptide , a nucleotide - binding oligomerization domain - containing protein 2 ( nod2 ) ligand , do not provoke such a response ( saitoh et al .
ligands that engage tlr4 and to some extent those recognized by tlr3 , tlr7 , and tlr9 , but not tlr2 or tlr5 , elicit enhanced il-1 in autophagy - deficient macrophages ( saitoh et al . , 2008 ) .
in murine macrophages , excessive cytokine production following autophagy shutdown requires tir - domain containing adapter inducing ifn ( trif ) , an adapter molecule for tlr signaling ( saitoh et al . , 2008 ) , while in human cells the response is dependent on p38 mitogen activated protein kinase ( mapk ) phosphorylation ( crisan et al . , 2011 ) .
excessive il-1 secretion in the absence of autophagy is not associated with alterations in nfb activation ( saitoh et al . , 2008 ) .
importantly , exaggerated inflammatory cytokine production in the absence of autophagy translates to the development of severe disease in vivo .
atg16l1-deficient mice display enhanced inflammatory infiltrates in the distal colon , elevated il-1 , and il-18 serum levels and reduced survival in a dextran sulfate sodium induced model of experimental colitis ( saitoh et al . , 2008 ) .
lc3b - deficient mice exhibit enhanced susceptibility to lps - induced lethality ( nakahira et al . , 2011 )
, while both lc3b - deficient and beclin1 mice have increased il-1 and il-18 serum levels in response to cecal ligation and puncture - induced sepsis ( nakahira et al . , 2011 ) .
in addition to il-1/il-18 , the type i ifn pathway is also susceptible to modulation by autophagy . again
the absence of a functional autophagy pathway promotes amplified secretion of type i ifn in response to a given stimulus .
vsv infection of atg5-deficient murine embryonic fibroblasts ( mef ) elicits increased production of ifn , ifn , il-6 , and ip-10 and as such dramatically attenuates viral replication rendering cells resistant to infection ( jounai et al .
another example is atg9a - deficient mef that exhibit enhanced ifn production in response to stimulation with inflammatory double stranded dna ( saitoh et al . , 2009 ) .
therefore , autophagy has the potential to exert a critical influence on the regulation of pro - inflammatory cytokine production and downstream effector mechanisms of innate immunity .
the ability of autophagy to limit inflammatory cytokine production renders it a target pathway for pathogens to activate as a strategy to facilitate replication .
hepatitis c virus ( hcv ) is an example of a pathogen that is proposed to do this .
if hcv infection occurs in the absence of a functional autophagy pathway , hcv viral replication is severely attenuated due to the corresponding activation of the type i ifn pathway . therefore
, hcv infection elicits active autophagy in the infected cell , limiting type i ifn production and enabling successful viral replication ( ke and chen , 2011 ) . triggering autophagy is therefore a putative mode of immune escape .
pro - inflammatory stimuli induce the transcription of inactive precursors pro - il-1 or pro - il-18 .
cleavage of the inactive proteins into their active secreted forms requires the assembly of an inflammasome , a large protein complex that , under inflammatory conditions , processes pro - caspase-1 to caspase-1 .
active caspase-1 then cleaves pro - il-1 and pro - il-18 liberating the active cytokines for secretion by the cell . in mouse cells ,
the levels of precursor il-1 are not altered following lps stimulation in the absence of autophagy ( saitoh et al . , 2008 ) , rather there is an increase in the cleaved form of caspase-1 ( saitoh et al . , 2008 ;
in contrast , in human cells , transcription of il-1 is elevated ( crisan et al . ,
a major role for autophagy in inflammatory cytokine secretion is considered to be via its contribution to maintaining a healthy intracellular environment .
namely , autophagy has a pivotal role in the clearance and elimination of damaged and dysfunctional organelles .
studies have demonstrated autophagic degradation of depolarized mitochondria ( sandoval et al . , 2008 ) , expanded endoplasmic reticulum ( bernales et al . , 2006 ) , mature ribosomes ( kraft et al . , 2008 ; kundu et al . ,
the role of autophagy in the maintenance of mitochondrial integrity is a process known as  mitophagy .  in the absence of functional mitophagy , cells accumulate damaged mitochondria that produce high levels of reactive oxygen species ( ros ) , a side product of cellular respiration ( zhou et al . , 2011 ) .
the accumulation of damaged mitochondria is further exacerbated following stimulation with inflammatory compounds as observed for lc3b or beclin 1-deficient macrophages treated with lps plus atp ( nakahira et al .
, 2011 ) . without the autophagy pathway to remove these dysfunctional organelles , ros levels increase ( saitoh et al . , 2008 ) , a known trigger for the nucleotide binding domain , leucine rich - containing family , pyrin domain containing 3 ( nlrp3 ) inflammasome ( zhou et al . , 2011 ) .
damaged mitochondria also display increased membrane permeability with mitochondrial dna ( mtdna ) then being able to translocate to the cytosol .
mtdna is detected in higher abundance in the cytosol of lc3b and beclin 1-deficient macrophages , most notably following stimulation with lps plus atp ( nakahira et al . , 2011 ) .
as such , autophagy , by acting to maintain turnover of damaged organelles and preserving mitochondrial integrity , indirectly restricts excessive inflammatory cytokine production by removing endogenous triggers of the inflammasome .
the second mechanism by which autophagy controls inflammatory cytokine activity is through its direct interaction with proteins involved in inflammatory cascades . in this case , proteins are targeted by autophagosomes or the autophagy machinery .
following inflammasome induction , components of the absent in melanoma 2 ( aim2 ) inflammasome associate with p62 and beclin1 and exhibit k63-linked ubiquitination ( shi et al . , 2012 ) .
other examples of the direct targeting of inflammatory proteins by autophagy include the co - localization of the autophagosomal protein lc3 and il-1 in punctate autophagosomal structures following stimulation of bone marrow - derived macrophages with a variety of tlr ligands including lps , pam3cys , poly ( i : c ) , r837 , or cpg ( harris et al . , 2011 ) .
the authors suggest that autophagy limits il-1 secretion by facilitating its degradation in the auto - lysosome . a direct role for autophagy in modulating components of the type i ifn response is illustrated by several examples where the autophagy machinery targets proteins involved in this signaling cascade .
atg5atg12 directly interacts with the cytosolic viral rna sensor rig - i and the signaling molecule ifn promoter stimulator-1 ( ips-1 ) .
interaction with atg5atg12 blocks caspase recruitment domain ( card)-mediated signaling and the downstream production of type i ifn ( jounai et al . , 2007 ) .
another interesting example is stimulator of interferon genes ( sting ) , a molecule critical for type i ifn signaling .
atg9a is critical for the localization of sting to cytoplasmic punctae following treatment of cells with dsdna ( saitoh et al . , 2009 ) .
mislocalization of sting to the endoplasmic reticulum results in exacerbated ifn responses ( saitoh et al . , 2009 ) , although the specific details of why this is the case remain to be elucidated .
in contrast to il-1 , il-18 and type i ifn , mouse tumor necrosis factor ( tnf) and il-16 ( harris et al . , 2011 ) , and human tnf ( crisan et al . , 2011 ) production is inhibited when autophagy is suppressed .
this is the case for macrophages following stimulation with lps or pam3cys in the presence of 3-ma .
another example is the reduced production of il-8 by intestinal epithelial cells with silenced atg7 ( li et al . , 2011b ) .
the mechanism of why these cytokine pathways require autophagy may involve autophagic inhibition of p38 phosphorylation ( crisan et al . , 2011 )
. therefore the role of autophagy in modulating cytokine output is complex with its contribution varying for individual cytokines . another mechanism by which autophagy modulates inflammation is by restricting the expression of extracellular inflammatory signals . during programmed cell death
, autophagy enables the generation of a cellular corpse that is efficiently phagocytized and less likely to elicit detrimental inflammatory outcomes .
this is elegantly illustrated in a model of embryonic cavitation , where apoptotic embryonic stem cells lacking atg5 or beclin1 fail to exhibit critical engulfment signals ( qu et al .
these include failing to expose phosphatidylserine ( ps ) at the outer membrane and lack of secretion of the chemoattractant lysophosphatidylcholine . as a consequence ,
autophagy - deficient cellular corpses are not engulfed for clearance by immune cells . the failure to eliminate autophagy - deficient apoptotic corpses
excess apoptotic corpses are detected in the lungs and retina , together with the presence of an abnormal inflammatory infiltrate in these tissues .
interestingly , atg5 ( uhl et al . , 2009 ) , beclin1 ( li et al . , 2008 ) , or atg12
2008 ) cells loaded with antigen are less efficient at facilitating dc antigen presentation to cd8 t cells ( cross - presentation ) .
the requirement for autophagy in the display of engulfment signals is thought to be due to the pathway s role in maintaining cellular bioenergetics .
restoration of atp levels in autophagy - deficient cells by treatment with methylpyruvate restores corpse clearance ( qu et al . , 2007 ) .
induction of autophagy in dying cells also stimulates the release of immune modulator high mobility group b1 ( hmgb1 ; thorburn et al . , 2009 ) that promotes immunogenicity and removal of apoptotic corpses ( scaffidi et al . , 2002 ) .
proteolysis provides the peptide epitopes displayed by major histocompatibility complex ( mhc ) molecules to elicit t cell responses .
all nucleated cells utilize the proteasome , a multiproteolytic complex located in the cytosol that generates ligands for mhci presentation . in mhcii expressing cells , lysosomal proteases generate ligands for these molecules .
autophagy participates in generating the pool of peptides displayed by mhcii molecules due to its role in trafficking cytosolic proteins to the lysosomes , the same compartment where biosynthesis and loading of mhcii molecules occurs .
indeed , the autophagosomal protein lc3 co - localizes with mhcii loading compartments in dc ( schmid et al . , 2007 ) .
fusion of influenza matrix protein m1 ( schmid et al . , 2007 ) or the hemagglutinin ( ha ) site 1 epitope ( comber et al . , 2011 ) to lc3 enhances their presentation by mhcii to cd4 t cells as a result of the intersection of autophagosomes and mhcii loading compartments .
autophagy contribution to mhcii antigen presentation is further supported by detailed analysis of the steady state mhcii repertoire where up to a third of peptides displayed by mhcii are shown to be derived from cytoplasmic or nuclear sources ( chicz et al . , 1993 ; dongre et al . ,
2001 ) and would potentially rely on autophagy trafficking to access the mhcii loading compartment .
induction of autophagy increases the relative display of these peptides compared to those derived from membrane proteins ( dengjel et al .
peptides derived from lc3b and gamma - aminobutyric acid receptor - associated protein ( gabarap ) , components of the autophagy machinery are eluted from mhcii molecules ( dengjel et al . , 2005 ) .
there is now a growing list of antigens that are documented as being trafficked by autophagy for mhcii display .
these include self proteins together with virus and bacterial - derived antigens ( munz , 2009 ) .
the role of autophagy in presenting self antigen by mhcii , means that autophagy contributes to cd4 t cell selection in the thymus .
studies in which atg5 thymi were grafted into normal recipients elegantly illustrate that autophagy trafficking in thymic epithelial cells participates in the display of self antigen by mhcii ( nedjic et al . , 2008 ) .
transplant of atg5-deficient thymi into mhcii - restricted tcr transgenic hosts results in reduced positive selection of ha and sep - specific cd4 tcr t cells .
selection of and , do11.1 , or dep - specific cd4 tcr transgenic t cells , on the other hand , proceeds efficiently in the absence of autophagy .
autophagy is therefore considered to facilitate the thymic mhcii presentation of some self proteins but not others . in doing so
, autophagy contributes to the complex composition of the repertoire of mhcii epitopes that are displayed by the thymic epithelium .
the role for autophagy in thymic selection is further evidenced by an increase in ie5268ia complexes at the surface of cortical thymic epithelial cells that lack atg5 ( nedjic et al . , 2008 ) . in this case
, it is postulated that the removal of autophagy dependent endogenous epitopes due to the absence of atg5 , reduces competition and increases access of the ie peptide to mhcii .
in addition to autophagy shaping the cd4 t cell repertoire that emerges from the thymus , it also participates in effective cd4 t cell immunity during infection .
autophagy dependent - mhcii presentation of cytosolic model antigens has been described for complement c5 ( brazil et al . , 1997 ) , tumor antigen mucin 1 ( dorfel et al . , 2005 ) and neomycin phosphotransferase ( nimmerjahn et al . , 2003 ) where presentation is inhibited following treatment with 3-ma .
nuclear antigen 1 of epstein - barr virus ( ebna-1 ) is a prominent example of a viral - derived antigen that requires autophagy for presentation by mhcii ( paludan et al . , 2005 ) .
treatment with 3-ma or silencing of atg12 inhibits ebna-1 specific cd4 t cells from recognizing a lymphoblastoid cell line ( paludan et al . ,
antigen presenting cell types that utilize autophagy to deliver antigen for mhcii presentation include b cells ( brazil et al . , 1997 ) , macrophages ( brazil et al . , 1997 ) , and
dc ( schmid et al . , 2007 ; jagannath et al . , 2009 ; lee et al . ,
autophagy - mediated delivery of antigen for mhcii presentation to cd4 t cells means that triggering autophagy represents a promising immunotherapeutic strategy to promote robust cd4 t cell responses .
indeed , immunization with rapamycin - treated dc , enhances mhcii presentation and cd4 t cell immunity to the anti - tuberculosis bcg vaccine antigen ( jagannath et al . , 2009 ) .
this is an exciting outcome , with major implications for improving vaccine efficacy in multiple settings . whether autophagy exhibits selectivity in the substrates targeted
this is important if the autophagy pathway is to be manipulated for delivery of antigen to mhcii .
while basal autophagy initiated under starvation conditions is considered to be a non - selective process , autophagy initiated under steady state conditions in immune cells is considered to be selective .
a general observation is that long lived proteins are considered to be turned over by lysosomal proteolysis and hence are autophagy substrates , while the proteasome degrades short lived polypeptides ( henell et al . , 1987 ) .
aggregates of long lived poly - ubiquitinated proteins are known substrates of autophagy ( mizushima and klionsky , 2007 ) . of interest ,
protein aggregates form in activated dc ( lelouard et al . , 2002 ) and in macrophages following tlr4 stimulation ( fujita et al . , 2011 ) .
autophagy receptors  have been described that act to recruit ubiquitinated proteins to autophagosomes via an lc3-interacting motif ( lir ) .
known autophagy receptors identified to date include p62/sequestosome1 ( komatsu et al . , 2007 ) , neighbour of brca1 ( nbr1 ) ( kirkin et al . ,
2009 ) , nuclear dot protein 52kda ( ndp52 ) ( thurston et al . , 2009 ) , and optineurin ( wild et al . , 2011 ) with all of these proteins possessing binding domains for both ubiquitin ( ubd ) and lc3 ( lir ) .
for example , p62 , optineurin , and ndp52 all target ubiquitinated salmonella enterica for destruction in lysosomes ( wild et al . , 2011 ) .
while optineurin and ndp52 colocalize , p62 binds to a separate subdomain of the ubiquitinated bacteria .
interestingly , optineurin is subject to phosphorylation by tank binding kinase ( tbk)1 , providing the molecular trigger to promote autophagic clearance of cytosolic bacteria ( wild et al . , 2011 ) .
identification of a growing number of autophagy receptors is exciting with the detail of the specific e3 ubiquitin ligases involved , the selective recognition of ubiquitin chains and their specific regulation by phosphorylation all remaining to be further studied .
somewhat unexpectedly , in addition to assisting the display of cytosolic antigen by mhcii molecules , autophagy also contributes to the presentation of extracellular antigen and phagocytosis .
individual components of the autophagy machinery are recruited to phagosomes in the presence of tlr signaling . during a process termed 
( sanjuan and green , 2008 ) , lc3 is recruited to latex - bead phagosomes in macrophages , when beads are coupled with the tlr agonists lps or pam3cys or in response to phagosomes containing killed yeast particles ( zymosan ; sanjuan et al . , 2007 ) .
lap also contributes to the phagocytosis of apoptotic , necrotic , or receptor interacting kinase-3 ( ripk3)-necrotic cells with this response being triggered by the t cell immunoglobulin and mucin domain containing molecule ( tim)4 receptor ( martinez et al . , 2011 ) .
entosis , the engulfment of live cells , also involves localization of lc3 to the entotic vacuole ( florey et al . , 2011 ) .
the recruitment of lc3 to phagosomes requires other components of the autophagy machinery given that it does not take place in the absence of atg5 ( sanjuan et al .
, 2007 ; martinez et al . , 2011 ) , atg7 ( sanjuan et al . , 2007 ; martinez et al . , 2011 ) , or beclin-1 ( martinez et al . , 2011 )
the role of autophagy in extracellular phagocytosis and mhcii antigen presentation is evident given that atg5-deficient dc show impaired mhcii presentation of soluble and cell - associated antigen and elicit impaired cd4 t cell responses in response to antigens derived from herpes simplex virus-2 ( hsv-2 ; lee et al . ,
infection of atg5-deficient mice with hsv-2 results in a failure of atg5-deficient mice to mount protective cd4 t cell immunity and enhanced disease progression occurs ( lee et al . ,
autophagy also contributes to exogenous processing and mhcii presentation of hiv-1-derived protein ( blanchet et al . , 2010 ) .
the autophagy machinery is considered to contribute to phagocytosis by facilitating phagosome to lysosome fusion and the delivery of lysosomal proteases to phagosomes , required for effective antigen degradation .
extracts of phagosomes isolated from atg5-deficient dc displayed impaired cathepsin ( cat ) s , catb / l activity when assayed with fluorogenic substrates ( lee et al . , 2010 ) .
a contribution of autophagy to mhci antigen presentation is less obvious , given that the major proteolytic source of peptide generation for mhci is the proteasome and not lysosomal proteases .
indeed , there are several reports discarding a role for autophagy in mhci presentation of antigen derived from extracellular sources ( cross - presentation ; blanchet et al .
one report demonstrates the requirement for autophagy in macrophage mhci presentation of glycoprotein b ( gb ) , a hsv-1-derived protein ( english et al . , 2009 ) .
in this case , treatment with 3-ma or silencing of atg5 reduced presentation of gb by macrophages late after infection .
gb is proposed to be trafficked from the nuclear envelope to the autophagosome from where its escapes for degradation by the proteasome and mhci display . whether this applies only to hsv-1 infection , macrophages , or
another example is the cross - presentation of antigen loaded al2o3 nanoparticles ( li et al . ,
mhci presentation of al2o3 nanoparticles loaded with ova is inhibited following 3-ma treatment or silencing of atg12 or beclin1 .
the mechanism is unknown , however internalized nanoparticles are shown to access autophagosomes that are considered to be immunogenic ( li et al . , 2008 ) .
autophagy may also impact mhci presentation by degrading mhci molecules themselves ( li et al . , 2010 ) .
an important contribution of autophagy to adaptive immunity is its cell intrinsic role in lymphocyte survival .
an active autophagy pathway operates in t cells , with autophagosomes detected , particularly following activation via the t cell receptor ( tcr ) ( espert et al .
analysis of t cell compartments in atg5-deficient mice illustrates a role for autophagy in mature t cell survival ( pua et al . , 2007 ) . while thymus cellularity is reduced in the absence of atg5 , thymocyte development is unperturbed . in the periphery ,
reduced numbers of cd4 and cd8 t cells are present in the spleen and lymph node .
the cd8 t cell compartment is more affected , with a large proportion of atg5-deficient cd8 t cells staining with annexin v , indicative of cells undergoing early apoptosis .
both cd4 and cd8 t cells that survive in the absence of atg5 display proliferative defects following tcr stimulation , with fewer cells undergoing division , and fewer divisions completed in response to anti - cd3 compared with wildtype t cells .
the proliferative defect is not rescued by anti - cd28 or il-2 and the cells display normal levels of tcr and upregulate t cell activation markers cd69 and cd25 .
a similar phenotype is observed in atg7lck - cre mice where the specific deletion of atg7 in the t cell lineage results in mostly normal thymocyte development , however cd4 and cd8 t cell numbers are greatly reduced in the peripheral lymphoid compartment .
both subsets of peripheral t cells display evidence of apoptosis ; with a large proportion staining with annexin v and exhibiting caspase 9 activity .
impaired t cell survival in the absence of autophagy is likely to arise from its pivotal role in maintaining intracellular organelle integrity .
atg7-deficient t cells possess increased numbers of mitochondria and increased ros levels ( pua et al . , 2009 ) .
for the b cell compartment , the absence of atg5 impairs b cell development in the bone marrow , with reduced survival of pre - b cells and consequently reduced numbers of mature b-1a cells in the periphery ( miller et al . , 2008 ) . in some settings
examples include autophagy - mediated t cell death following growth factor withdrawal ( li et al .
, 2006 ) and following binding of the hiv-1 envelope protein to c - x - c chemokine receptor 4 ( espert et al . ,
therefore , autophagy serves as a critical pathway in lymphocytes that facilitates the intricate balance between survival and death .
the critical impact of autophagy on effector functions of innate and adaptive immunity outlined herein , is highlighted by the association of autophagy gene mutations with increased incidence of inflammatory disease , susceptibility to microbial infection and autoimmune disease .
a prominent example is atg16l1 , a susceptibility gene for crohn s disease ( massey and parkes , 2007 ) , where the small intestine exhibits chronic inflammation triggered by a breakdown in the clearance of commensal bacteria .
atg16l1-deficient paneth cells possess elevated pro - inflammatory cytokine transcripts , while atg16l1-deficient mice develop exacerbated intestinal inflammation following environmental triggers , similar to that observed in human patients ( cadwell et al . , 2008 ) .
other examples include cystic fibrosis , a chronic inflammatory disease of the pulmonary airways , where autophagy - mediated maintenance of lung epithelial cell homeostasis is important to limit lung inflammation and disease ( luciani et al . , 2010 ) .
autophagy is also postulated to contribute to inflammation - associated responses underlying metabolic diseases , such as obesity ( yang et al . , 2010 ) . in infectious disease settings ,
irgm , a human immunity - related gtpase that plays a critical role in regulating autophagy - mediated clearance of mycobacteria , is a genetic risk factor for tuberculosis ( intemann et al . , 2009 ) . finally , a link between single nucleotide polymorphisms in the atg5 gene and susceptibility to systemic lupus erythematosus
, a debilitating autoimmune disease has been reported ( gateva et al . , 2009 ) .
the emergence of often surprising roles for autophagy in diseases of the immune system means that a wide range of immune - related diseases may now be amenable to targeting by autophagy modulating drugs . as such studies of autophagy in innate and adaptive pathways provide excellent insights into this complex pathway , uncovering new roles for autophagy in disease .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
 macroautophagy ( autophagy ) is a cellular pathway facilitating several critical functions . 
 first , autophagy is a major pathway of degradation . 
 it enables elimination of microbes that have invaded intracellular compartments . 
 in addition , it promotes degradation of damaged cellular content , thereby acting to limit inflammatory signals . 
 second , autophagy is a major trafficking pathway , shuttling content between the cytosol and the lysosomal compartment . given these two key roles , autophagy can have significant and sometimes unexpected consequences on mechanisms that initiate robust immunity . here , we will discuss the impact of autophagy on pathways of innate and adaptive immune responses including microbe elimination , inflammatory cytokine production , antigen processing and t and b lymphocyte immunity . 
Autophagy and Innate Effector Mechanisms
Autophagy and Adaptive Immunity
Autophagy and Disease
Conflict of Interest Statement