of July 5 2022This information is current as

Memory CD8 T CellsBystander-ActivatedChange in Perception of

The Ugly Duckling Turned to Swan A

Nicholas J Maurice Alexis K Taber and Martin Prlic

httpwwwjimmunolorgcontent2063455doi 104049jimmunol2000937

2021 206455-462 J Immunol

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is published twice each month byThe Journal of Immunology

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The Ugly Duckling Turned to Swan A Change inPerception of Bystander-Activated Memory CD8 T CellsNicholas J Mauricedagger Alexis K Taber and Martin PrlicDaggerx

Memory T cells (Tmem) rapidly mount Ag-specific re-sponses during pathogen reencounter However Tmem

also respond to inflammatory cues in the absence of anactivating TCR signal a phenomenon termed by-stander activation Although bystander activation wasfirst described over 20 years ago the physiological rel-evance and the consequences of T cell bystander acti-vation have only become more evident in recent yearsIn this review we discuss the scenarios that triggerCD8 Tmem bystander activation including acute andchronic infections that are either systemic or localizedas well as evidence for bystander CD8 Tmem withintumors and following vaccination We summarize thepossible consequences of bystander activation for theT cell itself the subsequent immune response andthe host We highlight when T cell bystander activa-tion appears to benefit or harm the host and brieflydiscuss our current knowledge gaps regarding regula-tory signals that can control bystander activationThe Journal of Immunology 2021 206 455ndash462

Ahallmark feature of adaptive immunity is the devel-opment of immunologic memory CD8 memoryT cells (Tmem) respond rapidly upon reencounter with

cognate Ag by acquiring effector function and initiating celldivision (1) Bystander activation of CD8 Tmem is driven byproinflammatory cytokines such as type I IFNs IL-12 IL-15and IL-18 and occurs in the absence of agonist TCR signalsThis has been demonstrated in mouse models using TCR-transgenic T cells as well as with polyclonal CD8 Tmem usingNur77-GFP reporter mice Briefly GFP expression is transientlyincreased in T cells of these reporter mice after the cells receive aTCR signal including those mediated by very weak agonists (2)Bystander-activated CD8 Tmem did not show increased GFPexpression demonstrating that bystander activation occurs in-dependently of (measurable) agonist TCR signals (3) Thusbystander activation of CD8 Tmem is a distinct phenomenon

from TCR cross-reactivity which can occur even in unrelatedinfections but is still TCR-mediated (4) The direct functionaloutcome of TCR-mediated versus bystander-mediated Tmem

activation appears remarkably similar and can in both instancesinclude T cell proliferation (5) cytokine expression (6ndash9) anddirect target cytolysis (3 10ndash12) The Ag-specific T cell responseis stringently regulated and requires two signals (TCR + co-stimulation) to allow for the initial activation of a naive T celland even a third signal (such as type I IFN or IL-12) for a CD8T cell to acquire effector function (13) Furthermore the du-ration of effector function is inherently limited as T cells acquireexpression of inhibitory proteins during the effector stage in-cluding expression of PD-1 and CTLA-4 (14) Prolonged acti-vation of T cells leads to T cell exhaustion (also referred to asT cell dysfunction) which is characterized by a TCR signalingndashdependent loss of the ability to proliferate or produce effectormolecules such as IFN-g in response to stimuli (15)Given that numerous regulatory mechanisms are in place to

tightly control the TCR-driven effector T cell response it raisesthe question why Tmem are seemingly easily activated by in-flammatory signals One could argue that control mechanismsto regulate bystander activation of Tmem may not be critical if itonly occurs in very rare and specific scenarios such as systemicviral infections which is how bystander activation was initiallydiscovered (5) Indeed it had been proposed that bystanderactivation is not of major biological consequence (16) A lack ofrelevance could be possible if bystander activation of Tmem wasa vestigial feature that stems from the gradual development ofthe adaptive immune system from the innate immune system(17) In this review we discuss the evidence that suggests thatbystander activation is neither a rare occurrence nor a vestigialfeature but a critical part of the early immune response to in-fection as well as the ongoing immune response during chronicinfections and other conditions of chronic inflammation

Niche phenomenon of systemic viral infections or regular occurrenceWhen and where T cell bystander activation occurs

Bystander activation of Tmem during acute systemic infections in miceand humans The first indication that CD8 Tmem become

Vaccine and Infectious Disease Division Fred Hutchinson Cancer Research CenterSeattle WA 98109 daggerMolecular and Cellular Biology Graduate Program Universityof Washington Seattle WA 98195 DaggerDepartment of Immunology University ofWashington Seattle WA 98109 and xDepartment of Global Health University ofWashington Seattle WA 98195

ORCIDs 0000-0002-2667-472X (NJM) 0000-0002-7012-3001 (AKT) 0000-0002-0685-9321 (MP)

Received for publication August 10 2020 Accepted for publication September 112020

This work was supported by National Institutes of Health Grant R01 AI123323 (to MP)and National Cancer Institute Grant 1F99CA245735-01 (to NJM) NJM is a Leslie

and Pete Higgins Achievement Rewards for College Scientists Fellow and Dr NancyHerrigel-Babienko Memorial Scholar

Address correspondence and reprint requests to Dr Martin Prlic Fred HutchinsonCancer Research Center 1100 Fairview Avenue N E5-110 PO Box 19024 SeattleWA 98109 E-mail address mprlicfhcrcorg

Abbreviations used in this article AHA acute hepatitis A GzmB granzyme B HAVhepatitis A virus IAV influenza A virus NKG2DL NKG2D ligand RA rheumatoidarthritis TME tumor microenvironment Tmem memory T cell TRM resident memoryT cell YFV yellow fever virus

Copyright 2021 by TheAmerican Association of Immunologists Inc 0022-176721$3750

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activated during an infection even in the absence of Ag wasmade by Tough and colleagues (5) when they reported that alarge fraction of CD8 Tmem proliferated in response to sys-temic infection with lymphocytic choriomeningitis virusvaccinia virus and vesicular stomatitis virus Based on thelarge fraction of CD8 Tmem that proliferated Tough et alhypothesized that proliferation was driven by type I IFNrather than Ag To test this hypothesis they induced a typeI IFN response by injecting mice with poly IC and againobserved that a substantial part of the Tmem populationproliferated and referred to it as bystander proliferationImportantly bystander proliferation was much more limitedcompared with Ag-driven proliferation as it appeared to onlyinduce one round of cell division (5 18) Whereas Ag-specificT cell expansion results in a substantial temporary increase ofthe T cell compartment during acute infections bystanderproliferation is seemingly providing little to no contributionto this increase in T cell numbers and also appears to have anegligible effect on the overall size of the Tmem compartment(18) Studies by Welsh and colleagues (19 20) suggested thatbystander activation could even lead to a net loss of Tmem

during heterologous infections Although these initialobservations of bystander activation focused primarily onproliferation subsequent studies found that bystander-activated CD8 Tmem also gained effector functionincluding the ability to secrete IFN-g and express granzymeB (GzmB) (3 7 8 21) which led to the shift in terminologyfrom bystander proliferation to bystander activationImportantly bystander activation of CD8 Tmem that arenot Ag specific has also been demonstrated during thecourse of systemic viral infections in human cohortsincluding primary HIV (22 23) primary EBV (24) and(to varying degrees) during acute dengue virus infections(25ndash27) In these latter human studies peptideMHCtetramers were used to distinguish Ag-specific frombystander-activated Tmem Of note using human T cellsspecific for chronic viral infections such as CMV and EBVto assess bystander activation must be done carefully becauseit is challenging to distinguish between bystander activationand activation as a result of local viral reactivation

Bystander activation of Tmem during acute localized infectionsBystander activation of CD8 Tmem is not limited to systemicviral infections Bacterial motifs can similarly elicit inflam-mation to bystander activate CD8 Tmem (28ndash30) as do sys-temic Listeria monocytogenes (3 6ndash9 31ndash33) and Yersiniapseudotuberculosis (33) infections Importantly recent studiesdemonstrate that bystander activation of CD8 Tmem alsooccurs during acute localized infections The initial splenicphase of a low-dose L monocytogenes infection (6) lunginfection with Staphylococcus aureus (34) or influenza Avirus (IAV) (21 35) all result in bystander activation ofCD8 Tmem at the site of infectionIn context of a low-dose L monocytogenes infection that was

delivered iv bystander activation of CD8 Tmem was observedwithin the first 24 h of infection These bystander-activatedT cells were specifically enriched in splenic white pulps withL monocytogenes lesions and expressed GzmB but did notexpress Ki-67 suggesting that they were not proliferating (6)The size of the bystander-activated CD8 Tmem populationincreased in the subsequent days but then declined substantiallybetween days 3 and 5 postinfection Similarly experiments that

challenged mice intranasally with LPS or heat-killed or livebacteria revealed that tissue resident memory T cells (TRM) lo-cated in the lung were bystander activated within 3 h of chal-lenge (34) Together these studies highlight that bystanderactivation occurs rapidly in the early stages of an immune re-sponse Although studying acute localized infections is easilyaccomplished in the mouse model system studying a definedlocalized primary infection is much more challenging in humancohorts A recent set of studies used liver biopsies from patientsdiagnosed with acute hepatitis A (AHA) and found evidence ofbystander activation of CD8 Tmem in these patients (10) Ofnote hepatitis A virus (HAV) does not cause chronic liver dis-ease but symptoms and inflammation can last for weeks and upto several months which raises the question if a state of by-stander activation is maintained in settings of prolonged chronicinflammation or chronic infections

Bystander activation of Tmem during chronic infections Animalmodels demonstrate that chronic Leishmania major (11 12)and Borrelia burgdorferi (36) infections result in prolongedbystander activation of CD8 Tmem at sites of infectionSimilarly bystander activation of CD8 Tmem was observed inpatients infected with hepatitis B virus (25 37) Two recentreviews provide a more detailed overview of bystander acti-vation in context of chronic infections (38 39) Althoughbystander activation of Tmem is observed in settings of chronicinflammation it is noteworthy that it is less clear how longthe state of bystander activation can last for a CD8 Tmem on asingle-cell level To our knowledge there are no studies thathave addressed whether a CD8 Tmem can remain bystanderactivated for prolonged periods of time Other possibilitiesinclude that bystander-activated CD8 Tmem could changeexpression of chemokine receptors and leave the site ofinflammation they could become nonresponsive toproinflammatory cytokines or have other regulatorymechanisms that would allow a return to steady stateBystander-activated CD8 Tmem could also undergoapoptosis or related forms of programmed cell death Thishas been observed in some mouse models of heterologousviral infections (19) in which chronic STAT1 signalingmediated by type I IFNs (20) or IL-6 (40) drives bystanderCD8 Tmem loss

Bystander activation of Tmem in other settings Although bystanderactivation has been predominantly studied in the context ofvarious infections there is also evidence for bystander acti-vation of CD8 Tmem by sterile inflammation vaccination andthe tumor microenvironment (TME) Evidence of bystanderactivation of CD8 Tmem has been observed in rheumatoidarthritis (RA) (41) and celiac disease (42) A recent study bySimoni and colleagues revealed the presence of bystanderCD8 Tmem including IAV- CMV- and EBV-specific T cellsin human solid tumors It is still unclear if these CD8 Tmem

are merely bystanders in the sense that they are not tumor-specific or if they are actually bystander activated and secreteIFN-g or other effector molecules (43) Finally recent evidencesuggests that im vaccination with a modified vaccinia Ankarandashbased vector elicits an inflammatory response that is sufficientto bystander activate CD8 Tmem in a human cohort and canbe measured 3 d postimmunization using a preimmunizationblood draw as a baseline (6) Another study examinedbystander activation following yellow fever virus (YFV) and

456 BRIEF REVIEWS OUTCOMES AND RELEVANCE OF MEMORY T CELL BYSTANDER ACTIVATION

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Dryvax vaccination and did not find evidence of bystanderactivation (44) However the earliest time points examined inin this latter study were days 9 and 11 following Dryvax andYFV administration respectively YFV immunization resultsin transient viremia that can be measured between days 3 and7 (44) Given that bystander activation of Tmem is transientand depends on the presence of inflammatory cues the lack ofbystander activation at time points past viremia is in line withmouse models of acute infection in which bystanderactivation is limited to the first few days of infectionTogether these studies indicate that bystander activation of

CD8 Tmem occurs over a wide range of inflammatory con-ditions including situations when inflammation is localizedand not pathogen induced

Bystander activation across CD8 Tmem subsets and in the early stage ofthe immune response

In contrast to Tmem cells there is no evidence that naiveT cells undergo bystander activation Instead naive CD8T cells become briefly activated in context of a systemic viralinfection or L monocytogenes infection but may undergoapoptosis without a subsequent TCR signal (20 45) Type IIFN was the first signal identified as sufficient to induce by-stander proliferation of Tmem but it can also lead to bystanderactivation (21) In addition to type I IFN at least two of thefollowing cytokines in combination are sufficient to triggerbystander activation IL-12 IL-15 IL-18 (6ndash8 30 46ndash48)or TLR2 signaling (36) (Fig 1A) Freeman and colleagues(46) tested over 43 murine cytokines in over 1800 differentcytokine combinations to induce TCR-independent IFN-gproduction in a rather heroic effort of identifying additionalcytokine combinations that can elicit or diminish bystanderactivation of CD8 Tmem The resulting data were complexand highlighted the importance of defining the cytokinecomposition of an inflammatory environment to understandwhy a Tmem cell did or did not acquire a bystander-activatedphenotypeMeasuring IFN-g secretion and GzmB expression is cer-

tainly useful to assess bystander activation but it is importantto consider that other functional properties cell fate etc maychange as well but these potential changes have not beenextensively investigated to date Similarly how proin-flammatory signals affect different Tmem subsets is poorlyunderstood Although this brief review is focused on by-stander activation of CD8 Tmem other reviews provide anoverview of how CD4 Tmem (36) and mucosal-associatedinvariant T cells (49 50) can become bystander activatedProinflammatory cytokines also activate invariant NKT cells(51 52) and gd T cells (53) in the absence of cognate Ag Thenotion that cytokine signals may elicit different functionalprograms is particularly relevant for CD4 Tmem given theirfunctional breadth (54) Importantly bystander activation isnot necessarily homogenous within or across CD8 Tmem

subsets The phenotype of a CD8 Tmem is shaped by its initialAg-driven encounter (55) variable expression of cytokinereceptors across Tmem subsets which is further affected byprevious Ag experience (56) and T cell responses to proin-flammatory cytokines such as IL-12 can also vary by biologicsex (57) Following infection with L monocytogenes a signif-icant fraction of bystander-activated (ie GzmB-expressing)CD8 Tmem had an effector memory phenotype but bystander

activation was also observed in CD8 Tmem with a centralmemory (CD62L+) phenotype (6) In this L monocytogenesmodel splenic CD8 TRM showed only limited bystanderactivation but splenic CD8 TRM may not be representative ofCD8 TRM in other tissues (34) Together these data dem-onstrate that within the CD8 Tmem compartment there ismemory subset and tissue compartment heterogeneity in by-stander activationCD8 T cells with a memory phenotype are not necessarily

generated by previous exposure to Ag Virtual CD8 Tmem cellsacquire a memory phenotype because of homeostatic prolif-eration (58) Virtual CD8 Tmem cells also become bystanderactivated during heterologous infection in an IL-15ndashdependentmanner (32) suggesting that bystander effector programs arenot exclusive to CD8 Tmem that have been expanded by AgWhite and colleagues provided intriguing evidence that avirtual memory T cellndashlike population also exists in humansand accumulates with age (32) Given the age-associated in-crease of memory T cells in humans over time (32) deter-mining how different Tmem subsets contribute to and affectimmune responses in the elderly in a TCR-independentmanner is of great clinical interestTogether these studies highlight that most CD8 Tmem

subsets are capable of becoming bystander activated and thatthis is in part dictated by cytokine receptor expression levelsand may be further shaped by the tissue microenvironment

Evidence for a role of bystander-activated CD8 Tmem in orchestratingthe initial immune response during acute inflammation

Professional APCs and other innate cells are thought to have akey role within the first 24 h of infection as the initial source ofIFN-g (59) Tmem have so far not been commonly associatedwith contributing to the early stages of an immune responsewhich may be related to the fact that mice are kept in specificpathogen-free environments and typically used for experi-ments at 6ndash10 wk of age when they still have a rather limitedTmem compartment This may have led to underestimatingthe role of bystander-activated Tmem in this early phase of animmune response Studies using ldquodirty micerdquo will help mimica more human-like environmental exposure while maintain-ing the other advantages of the mouse model system (60)Bystander-activated CD8 Tmem are observed during the

earliest stages of infection well before Ag-specific T cell re-sponses arise (3 6 7 31) Some CD8 Tmem are spatiallypositioned within lymph nodes to facilitate interactionswith pathogen-sensing phagocytes (61) and CD8 Tmem

can be bystander activated in tissues in situ (34) (Fig 2A)Moreover bystander CD8 Tmem can also relocate to sitesof early infection (6 35 62 63) A recent study dem-onstrated that bystander CD8 Tmem are recruited to earlysites of L monocytogenes replication in a CXCR3-dependent manner (Fig 2B) (6) This CXCR3-mediatedrelocation resulted in dense clusters of bystander-activatedCD8 Tmem that circumscribed L monocytogenes lesions asassessed by immunofluorescence (6) Remarkably thisCXCR3-dependent recruitment mechanism mirrors thatof Ag-specific T cells (64) and bystander-activated Tmem

and Ag-specific T cells can overlap spatially and tempo-rally (6) In context of L monocytogenes infection thefrequency of bystander-activated CD8 Tmem wanes as Ag-specific T cells start to accumulate in areas of infection at

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sim5 d postinfection (6) Similarly the frequency of bystander-activated CD8 Tmem declines as Ag-specific cells infiltrateIAV-infected lungs (62) suggesting that bystander-activatedCD8 Tmem begin to stand down as Ag-specific cytotoxicT cells take over Because bystander-activated CD8 Tmem

secrete IFN-g and express GzmB they inevitably affect theearly immune response which in turn will shape the subsequentadaptive immune response The impact of bystander-activatedCD8 Tmem on a developing Ag-specific T cell response hasnot been assessed but will likely depend on several factorsincluding the site of inflammation the extent of inflamma-tion and the availability of Ag

How bystander-activated CD8 Tmem shape the subsequentimmune response

Consequences of IFN-g secretion for the early immune response Ingeneral IFN-g has been shown to activate microbicidal ef-fector programs in macrophages and other APCs includingproduction of reactive oxygen species increased phagocytosis

and upregulation of Ag presentationcostimulatory moleculesto generate Ag-specific T cell responses (31 34 65) and isthus a central cytokine of the hostrsquos immune response Mousemodel studies with L monocytogenes have been leveraged todissect the importance of direct and indirect IFN-g effectsIFN-g responses are critical to coordinate primary immuneresponses against L monocytogenes (66) During the innatephase of L monocytogenes infection IFN-gndashdeficient micesuffer from a markedly higher splenic L monocytogenes burdenhowever the adoptive transfer of a wild-type bystander CD8Tmem population dramatically lowers L monocytogenes burdenat this timepoint (7) This phenomenon is a result of IFN-gderived from transferred bystander CD8 Tmem that becameactivated orchestrating effector responses in nearby APCs (31)(Fig 1) IFN-g signaling leads to an increase in phagocytosisand production of reactive oxygen species by APCs (31)which can directly limit L monocytogenes replication(67ndash69) APCs also increase Ag presentation and expressionof costimulatory molecules (31) which are critical signals for

FIGURE 1 Effector functions of bystander-

activated CD8 Tmem (A) Proinflammatory cy-

tokines including type I IFN or combinations

of IL-12 IL-15 andor IL-18 activate CD8

Tmem to become bystander activated and express

IFN-g andor GzmB (B) IFN-g could signal in

an autocrine and paracrine manner Both non-

immune cells (such as stromal and parenchymal

cells) and leukocytes (such as CD8 T cells

APCs and neutrophils) can be activated by

IFN-g (C) Engagement of NKG2D on bystander-

activated CD8 Tmem with stress-induced

NKG2DLs on targets coordinates the delivery

of cytotoxic GzmB granules to target cells

(D) IFN-g secretion has pleiotropic effects

which result in a heightened immune state

(E) Direct NKG2D-mediated and indirect

IFN-gndashmediated responses ultimately con-

verge to result in target cell death

458 BRIEF REVIEWS OUTCOMES AND RELEVANCE OF MEMORY T CELL BYSTANDER ACTIVATION

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priming Ag-specific T cells Ge and colleagues (34) recentlyreported that the early burst of IFN-g production bybystander CD8 TRM recruited neutrophils which in turnlimited S aureus growth during the first 3 d of bacterialpneumonia Of note CD8 T cellndashderived IFN-g that isavailable in the first 24 h of an infection can restrict Ag-specific effector CD8 T cell differentiation in a paracrinemanner resulting in an altered effector to memory balance(70) Furthermore IFN-g could also act in an autocrinemanner on CD8 Tmem (Fig 1) Together this suggests thatIFN-g derived from bystander-activated CD8 Tmem interactsupstream and downstream of the innate immune system tocontrol early pathogen replication

GzmB-mediated killing without cognate Ag GzmB codeliverywith perforin to a target cell results in its apoptotic death butthis cytotoxic payload poses risk to nearby cells (71) Ag-specific CD8 T cells secrete GzmB at the immunosynapseformed by their TCRs and cognate AgMHC class I ontargets minimizing the chance of GzmB uptake byunintended targets (71 72) So how can GzmB-expressingbystander CD8 Tmem kill or identify target cells in theabsence of cognate Ag This remained unclear until it wasshown that bystander-activated CD8 Tmem can identify andkill target cells in an NKG2D-dependent manner (Fig 1C1E) (3) The immunoreceptor NKG2D engages a suite ofstress-induced NKG2D ligands (NKG2DLs) which serve asgeneralized signals of infection stress or transformation(73ndash75) NKG2D is used by NK cells to survey for andeliminate NKG2DL-expressing cells In vivo blockade ofNKG2D-NKG2DL interactions led to increased bacterialloads early after infection even in the absence of NK cellsindicating that bystander-activated CD8 Tmem are needed toeliminate L monocytogenesndashinfected APCs expressingNKG2DLs (3)Numerous studies have documented the benefit of effector

responses by bystander-activated CD8 Tmem in multiple an-imal models of infection including L monocytogenes (3 7 3233) IAV (35 76) Y pseudotuberculosis (33) murinegammaherpesvirus 4 (77) and S aureus pneumonia (34)Together these studies suggest that the role of bystander-activated CD8 Tmem during an acute infection is to helpminimize pathogen spreading Given the timing of how by-stander activation appears to resolve when the Ag-specificT cell response takes over it seems that this mechanismcould help minimize the risk that the pathogen outruns host

immunity before the Ag-specific adaptive immune responsekicks in

Evidence for a role of bystander-activated CD8 Tmem in contributingto pathology during conditions of prolonged inflammation

Although NKG2D-dependent killing can help control earlypathogen spread during an acute infection this mechanism wassubsequently identified to cause immunopathology in contextof chronic infections (11 12) as well as human AHA (10)During AHA both HAV-infected and -uninfected hepato-cytes upregulate NKG2DLs (10) Bystander-activated CD8Tmem maintain high NKG2D expression especially in thepresence of IL-15 and can target NKG2DL-expressing he-patocytes whereas TCR stimulation downregulates NKG2Dexpression in HAV Agndashspecific T cells (10) Bystander-mediated killing of NKG2DL-expressing cells in vitrostrongly correlated with measures of liver damage in AHApatients highlighting the probable role of bystander-activatedCD8 Tmem in off-target damage (10) However it is unclearwhether these innate-like killing mechanisms although ca-pable of off-target damage contribute to HAV clearanceDuring chronic cutaneous leishmaniasis bystander CD8Tmem are recruited to infected tissues express GzmB but failto upregulate IFN-g (11) Stromal cells within L majorndashinfected ears uniformly upregulated NKG2DLs which renderedthem susceptible to NKG2D-mediated killing (11 12) NKcell depletion did not alter pathology whereas CD8 T celldepletion andor NKG2D blockade dramatically reducedtissue pathology (11 12) The notion that bystander-activatedCD8 Tmem use NKG2D to kill target cells in a mannersimilar to NK cells somewhat blurs the adaptive-innate di-chotomy but NK cells and bystander-activated CD8 Tmem

appear to have distinct roles because bystander-activated CD8Tmem were the main driver of NKG2D-dependent pathologyin context of chronic infection (11) and responsible forNKG2D-dependent early pathogen control following acuteinfection (3)Similar to chronic infections bystander-activated CD8

Tmem are also implicated in contributing to pathology inautoimmune diseases The signals that drive bystander acti-vation may be different in these scenarios Pathologically highlevels of IL-15 are found in affected tissues from patients withceliac disease (42 78) and RA (79 80) among other auto-immune disorders [reviewed by Jabri and Abadie (81)] ThisIL-15 exposure dually enhances the direct cytotoxicity of

FIGURE 2 Site-specific bystander

activation results in localized bystander-

mediated effector responses (A) Local-

ized infection will lead to the generation

of proinflammatory cytokines that can

bystander activate CD8 TRM in situ (B)

CXCR3 ligands (CXCR3L) including

CXCL9 and CXCL10 are produced at

sites of early immune activation Circu-

lating bystander CD8 Tmem are recruited

in a CXCR3-dependent manner to these

sites in which they encounter bystander-

activating cytokines (A and B) Both re-

sult in localized bystander activation and

bystander-mediated effector responses

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bystander-activated CD8 Tmem by upregulating GzmB (82) aswell as the NKG2D immunoreceptor (83) which is needed toeliminate NKG2DL-expressing targets During high IL-15exposure the enhanced cytotoxic potential of bystander-activated CD8 Tmem paired with aberrant expression ofNKG2DL in affected tissues biases for bystander-mediatedcytopathies in celiac disease (42) and RA (41) Althoughbystander-activated CD8 Tmem can kill NKG2DL-expressingtargets and propagate autoimmune damage when exposed topathologically high levels of inflammation these proin-flammatory cues must be maintained to sustain bystanderactivation Withdrawal of bystander-activating cytokines canabrogate the cytolytic potential of bystander-activated CD8Tmem in vitro (84) highlighting the critical role for IL-15 inthis context

Evidence for a role of bystander-activated CD8 Tmem inantitumor activity

TMEs with a lymphocyte infiltrate are also a type of chronicallyinflamed tissue Bystander CD8 Tmem infiltrate the TME inwhich they can even outnumber tumor-specific T cells andmay be distinguished from tumor Agndashspecific cells via lowCD39 expression (43 85 86) Although murine tumor Agndashspecific T cells within the TME are typically refractory tostimulation with cognate Ag and cannot be rescued by PD-1blockade bystander CD8 Tmem within the tumor maintainresponsiveness spared by their lack of tumor Ag specificity(87)NKG2D-mediated killing by NK cells and IFN-g secretion

by either tumor Agndashspecific T cells and NK cells can con-tribute to solid tumor clearance (88 89) Because bystander-activated CD8 Tmem can also employ these mechanisms theycould play a role in antitumor immunity Indeed recentmouse model studies demonstrate that bystander CD8 Tmem

can contribute to tumor clearance once appropriately acti-vated Intratumoral injection of the cognate peptide Ag forbystander CD8 Tmem can elicit IFN-g production and limittumor growth in vivo (90) Other studies demonstrate thatbystander-activated CD8 Tmem can kill tumor cells in anAg-independent manner in vitro (91ndash93) Bystander CD8+

virtual Tmem become activated and upregulate GzmB uponexposure to tumor cells pretreated with chemotherapeuticsthat target DNA replication (94) and directly killed MHCclass Indashdeficient targets in a GzmB-dependent manner in vitro(94) Of note there is strong evidence that recognition of self-antigenMHC is still required for bystander activation (95)Whether self-antigenMHC is only required for activation oralso to sustain effector function remains to be determined butis particularly relevant for understanding the antitumor po-tential of bystander-activated T cells Although the ability toleverage bystander-activated CD8 Tmem as a therapeutic mo-dality may hinge on the subset and history of these cells (96)these data highlight the potential therapeutic promise of acti-vated bystander CD8 Tmem Furthermore this underscores theimportance of understanding the yet to be identified cues thatpermit and regulate bystander-mediated effector functions

Evidence for regulatory mechanisms to control bystander-activatedCD8 Tmem

CD8 T cell exhaustiondysfunction has been proposed to be afunctional adaptation to allow for mediating some pathogen

control during chronic infections while minimizing tissuedamage (97) Similarly bystander-mediated pathologies dur-ing chronic infections may be acceptable collateral damage tohelp limit pathogen spread Although mechanisms that con-trol and turn off Ag-specific T cell responses have beenstudied extensively relatively little is known in regards tomechanisms that curb bystander activation Bystander-activated CD8 Tmem appear to be more susceptible to re-straint by anti-inflammatory cytokines including IL-10 thanTCR-activated T cells (98) Notably this IL-10 pathway isdisrupted in a model in which TLR2-mediated bystanderactivation contributes to Lyme arthritis (36) Thus althoughTLR2-agonizing pathogen-associated molecular patterns per-sist in joints affected by Lyme arthritis (99) immunoregula-tory cytokines may attenuate improper bystander activationand downstream pathologiesTCR-mediated activation of T cells also elicits the expression

of proteins with inhibitory function such as PD-1 and CTLA-4and thus provide a cell-intrinsic negative feedback signal tohelp turn off the T cell response Importantly IL-15 amongother common g-chain cytokines can induce PD-1 expres-sion on CD8 Tmem in vitro (100) Whether this can serve as acell-intrinsic negative signal in the absence of a TCR signal isunclear A combination of IL-12 IL-15 and IL-18 was suf-ficient to induce surface CTLA-4 expression on mucosal-associated invariant T cells in the absence of a TCR signalbut did not have the same effect on CD8 Tmem (101) Thesedata highlight that bystander activation has T cell subsetndashspecific effects that require further studies Together thesedata suggest cell-intrinsic and -extrinsic mechanisms may existto limit bystander activation

ConclusionsCD8 Tmem populations that can be bystander activated byinflammation are aplenty conventional Tmem virtual Tmemand TRM all demonstrate the propensity to mount effectorresponses in an Ag-independent inflammation-dependentmanner During localized acute infection bystander-activatedTmem help orchestrate the early immune response via secretionof IFN-g while simultaneously limiting pathogen spread viadirect target cytolysis These bystander responses are mountedin the first hours of infection and are highly spatially coor-dinated Thus bystander-activated CD8 Tmem can be con-sidered a ldquofirst responderrdquo amplifying the early immuneresponse and preceding appearance of Ag-specific T cells Onthe flipside continuous bystander activation of CD8 Tmem

exacerbates tissue damage causing immunopathologies Onlyvery few studies have addressed how effector functions ofbystander-activated CD8 Tmem are turned off but a betterunderstanding of these mechanisms will help to leverage by-stander CD8 Tmem therapeutically whether the goal is toenhance bystander activation to improve antitumor immunityor to diminish their function in context of autoimmunity

DisclosuresThe authors have no financial conflicts of interest

References1 Prlic M M A Williams and M J Bevan 2007 Requirements for CD8

T-cell priming memory generation and maintenance Curr Opin Immunol19 315ndash319

460 BRIEF REVIEWS OUTCOMES AND RELEVANCE OF MEMORY T CELL BYSTANDER ACTIVATION

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memory CD8 T cells and functional memory during acute and persistent viralinfections J Immunol 172 3139ndash3150

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The Journal of Immunology 461

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81 Jabri B and V Abadie 2015 IL-15 functions as a danger signal to regulatetissue-resident T cells and tissue destruction Nat Rev Immunol 15 771ndash783

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85 Canale F P M C Ramello N Nunez C L Araujo Furlan S N BossioM Gorosito Serran J Tosello Boari A Del Castillo M Ledesma C Sedlik et al2018 CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cellsCancer Res 78 115ndash128

86 Duhen T R Duhen R Montler J Moses T Moudgil N F de MirandaC P Goodall T C Blair B A Fox J E McDermott et al 2018 Co-expressionof CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tu-mors Nat Commun 9 2724

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89 Guerra N Y X Tan N T Joncker A Choy F Gallardo N XiongS Knoblaugh D Cado N M Greenberg and D H Raulet 2008 NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous ma-lignancy [Published erratum appears in 2008 Immunity 28 723] Immunity 28571ndash580

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93 Monjazeb A M J K Tietze S K Grossenbacher H H Hsiao A E ZamoraA Mirsoian B Koehn B R Blazar J M Weiss R H Wiltrout et al 2014Bystander activation and anti-tumor effects of CD8+ T cells following Interleukin-2based immunotherapy is independent of CD4+ T cell help PLoS One 9 e102709

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98 Freeman B E C Meyer and M K Slifka 2014 Anti-inflammatory cy-tokines directly inhibit innate but not adaptive CD8+ T cell functions J Virol88 7474ndash7484

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462 BRIEF REVIEWS OUTCOMES AND RELEVANCE OF MEMORY T CELL BYSTANDER ACTIVATION

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