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VACCINES
MAIT cell activation augments adenovirus vectorvaccine
immunogenicityNicholas M. Provine1*, Ali Amini1, Lucy C. Garner1,
Alexandra J. Spencer2, Christina Dold3,Claire Hutchings4, Laura
Silva Reyes3, Michael E. B. FitzPatrick1, Senthil
Chinnakannan4,Blanche Oguti3, Meriel Raymond3, Marta Ulaszewska2,
Fulvia Troise5,6, Hannah Sharpe2,Sophie B. Morgan7, Timothy S. C.
Hinks7, Teresa Lambe2, Stefania Capone8, Antonella Folgori8,Eleanor
Barnes1,2,4, Christine S. Rollier3, Andrew J. Pollard3, Paul
Klenerman1,4*
Mucosal-associated invariant T (MAIT) cells are innate sensors
of viruses and can augment early immuneresponses and contribute to
protection. We hypothesized that MAIT cells may have inherent
adjuvantactivity in vaccine platforms that use
replication-incompetent adenovirus vectors. In mice and
humans,ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly
activated MAIT cells. Activation requiredplasmacytoid dendritic
cell (pDC)–derived interferon (IFN)–a and monocyte-derived
interleukin-18.IFN-a–induced, monocyte-derived tumor necrosis
factor was also identified as a key secondary signal.All three
cytokines were required in vitro and in vivo. Activation of MAIT
cells positively correlated withvaccine-induced T cell responses in
human volunteers and MAIT cell–deficient mice displayed
impairedCD8+ T cell responses to multiple vaccine-encoded antigens.
Thus, MAIT cells contribute to theimmunogenicity of adenovirus
vectors, with implications for vaccine design.
Mucosal-associated invariant T (MAIT)cells are unconventional T
cells thatrecognizemicrobe-derivedmetabolitesof vitamin B2
biosynthesis such as5-(2-oxopropylideneamino)-6-D-
ribitylaminouracil (5-OP-RU) (1). However,MAIT cells can also be
activated by cytokinesand thereby respond to viruses, which do
notsynthesize vitamin B2. In vivo, MAIT cellsrespond to influenza
virus to amplify earlylocal immune responses and protect
againstlethal infection (2–4). We hypothesized that theability of
MAIT cells to augment early immuneresponses may play a key role in
viral vector vac-cine immunogenicity.
Replication-incompetentadenovirus (Ad) vectors are highly
potentvaccine platforms for many human diseases(5). They have
recently been licensed for useagainst the Ebola virus (6) and show
promisefor severe acute respiratory syndrome coro-navirus 2
(SARS-CoV-2) infection (7, 8). Wesought to determine whether such
vectorsactivate MAIT cells and whether this affectsvaccine
immunogenicity.To determine whether MAIT cells respond
to Ad vectors, we stimulated human periph-eral bloodmononuclear
cells (PBMCs) with Ad5and chimpanzee adenovirus Ox1 (ChAdOx1),
which are leading SARS-CoV-2 candidate vac-cines (7, 8). ChAdOx1
induced dose-dependentup-regulation of CD69, granzyme B, and
inter-feron (IFN)–g by MAIT cells (Fig. 1, A to C, andfig. S1, A to
D), whereas Ad5 only weakly ac-tivated MAIT cells. This activation
was con-firmed using the MR1–5-OP-RU tetramer toidentify MAIT cells
(fig. S1E).Species C–derived Ad vectors have been
shown to poorly stimulate innate immuneresponses as compared
with non–species Cvectors (9–11). We tested the relative ability
ofthree species C vectors (Ad5,Ad6, andChAdN13)and five non–species
C vectors (Ad24, Ad35,ChAd63, ChAd68, and ChAdOx1) (fig. S1F)
toactivate MAIT cells. After stimulation, we ob-served greater
average activation by non–species C vectors as compared with
speciesC vectors (Fig. 1, D and E).We next tested the ability of Ad
vectors to
activate MAIT cells in vivo. Intramuscular(i.m.) ChAdOx1
immunization of C57BL/6Jmicestrongly induced up-regulation of CD69
andgranzyme B by MAIT cells, whereas Ad5 in-duced significantly
weaker activation (Fig. 1, Fand G, and fig. S2, A to C). We also
observedsignificant up-regulation of CD69 onMAIT cells1 day after
immunization of human volunteerswith a candidate ChAdOx1 vaccine
(Fig. 1Hand fig. S3, A to C). Plasma IFN-g levelsmarkedly increased
after vaccination (fig.S3D), as seen in nonhuman primates (10).This
increase correlated with levels of MAITcell activation (Fig. 1I).To
investigate the pathways involved, RNA
sequencing (RNA-seq) of MAIT cells was per-formed. Eighty-four
genes were significantlyup-regulated in human MAIT cells after
vac-cination (Fig. 2A and data S1). Gene set en-richment analysis
(GSEA) (12) identified the
strong induction of type I IFN, interleukin(IL)–1 family, IL-12
family, and IL-2 familysignaling pathways (Fig. 2B). Changes in
post-vaccination plasma IFN-a or CCL2, an IFN-regulated chemokine
(13), strongly correlatedwith MAIT cell activation (Fig. 2C and
fig. S3,D and E). Comparison of genes up-regulatedin MAIT cells
after human vaccination, vacci-nation of mice, or in vitro
stimulation showeda high degree of overlap. Ninety-eight percentof
vaccine–up-regulated genes in humans wereup-regulated in at least
one of the other twoconditions, and 63%were up-regulated in
both(Fig. 2D; fig. S4, A and B; and data S2 to S4).GSEA on murine
MAIT cells and in vitro–stimulated human MAIT cells identified
sim-ilar enrichment of these cytokine signalingpathways (fig. S4, C
and D).In vitro inhibition of type I IFN signaling
reduced MAIT cell IFN-g production by >50%(Fig. 2E). Blockade
of IL-18 (an IL-1 familymember) or IL-12 also reduced MAIT
cellactivation. By contrast, blockade of IL-15 (anIL-2
familymember) had no effect (Fig. 2F andfig. S5A). MAIT cell
activation by Ad vectorswas independent of T cell receptor
signaling(fig. S5B) (2, 3).To understand the cellular origins of
these
critical cytokines, we examined the cell popu-lations
transducedbyAd5 andChAdOx1.Mono-cytes or conventional dendritic
cells were themajor transduced population by both vectors[>80%
of green fluorescent protein–expressing(GFP+) cells] (fig. S5, C to
F). ChAdOx1 alsoefficiently transduced CD123+ plasmacytoiddendritic
cells (pDCs), whereas Ad5 did not(fig. S5F) (11). Notably,
depletion of CD123+
pDCs resulted in a significant (67%) reduc-tion in IFN-g
production by MAIT cells (Fig.2G) and reduced IFN-a levels by
>99% afterChAdOx1 stimulation (Fig. 2H).Depletion of CD14+
monocytes significantly
reduced MAIT cell activation after ChAdOx1stimulation (Fig. 2I
and fig. S5G) and abro-gated the secretion of IL-18 (Fig. 2J).
Thecathepsin B–NLRP3 inflammasome pathway(14) was the source of
IL-18 in response toChAdOx1 (fig. S6). Thus, pDC-derived
IFN-aandmonocyte-derived IL-18 play critical rolesin activating
MAIT cells in response to Advectors. Ad5 induced negligible amounts
ofIFN-a (fig. S7, A and B) (10, 11). Despite trans-ducing
monocytes, Ad5 did not induce IL-18or IL-12p70 (fig. S7, C and D).
By contrast,ChAdOx1 induced robust production of IFN-aand
IL-18.Although IFN-a/b and IL-18 together in-
duced production of IFN-g by MAIT cells inPBMC culture, this was
not seen using iso-lated CD8+ T cells [~75% of humanMAIT
cellsexpress CD8 (15)] (Fig. 3A), despite the in-duction of CD69
(fig. S8A). Depletion ofmono-cytes reduced MAIT cell IFN-g
productionafter stimulation with IFN-a and IL-18 (fig.
RESEARCH
Provine et al., Science 371, 521–526 (2021) 29 January 2021 1 of
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1Translational Gastroenterology Unit, Nuffield Department
ofMedicine, University of Oxford, Oxford, UK. 2Jenner
Institute,University of Oxford, Oxford, UK. 3Oxford Vaccine
Group,Department of Paediatrics, University of Oxford, and
theNational Institute for Health Research (NIHR) OxfordBiomedical
Research Centre, Oxford, UK. 4Peter MedawarBuilding for Pathogen
Research, University of Oxford, Oxford,UK. 5Nouscom, SRL, Rome,
Italy. 6Ceinge BiotechnologieAvanzate, Naples, Italy. 7Respiratory
Medicine Unit, NuffieldDepartment of Medicine – Experimental
Medicine, Universityof Oxford, Oxford, UK. 8ReiThera, SRL, Rome,
Italy.*Corresponding author. Email:
[email protected](N.M.P.); [email protected]
(P.K.)
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S8B). The addition of monocytes rescuedthe response (Fig. 3B).
Conditioned super-natant or the provision of PBMCs across
atranswell significantly rescued MAIT cellIFN-g production (Fig. 3C
and fig. S8C), sug-gesting the presence of a soluble,
monocyte-derived, IFN-a–dependent signal.
Unexpectedly,IFN-a–treated monocytes secreted tumor ne-crosis
factor (TNF) (Fig. 3D and fig. S8D).Additionally, TNFR2 signaling
pathwayswere strongly induced in stimulated MAITcells (fig. S8, E
to G). Thus, we investigatedwhether TNF was the IFN-a–dependent
in-termediary signal. Addition of TNF or ananti-TNFR2 agonist to
isolated CD8+ T cellsstimulated with IFN-a and IL-18 enhancedMAIT
cell IFN-g production by >300% (Fig.3E and fig. S8H). Addition
of an anti-TNFantibody (adalimumab) inhibited MAIT cellIFN-g
production in response to IFN-a andIL-18 stimulation or to
conditioned super-natant (fig. S8, I and J). TNF blockade
usingeither adalimumab or recombinant TNFR2-Fcfusion protein
(etanercept), but not a controlantibody (vedolizumab), inhibited
IFN-g pro-duction byMAIT cells in response to ChAdOx1(Fig. 3F).
Depletion of monocytes reducedChAdOx1-induced TNF production by
94%(Fig. 3G). Ad5 inducedminimal TNF (fig. S8K),consistent with the
poor ability to stimulateIFN-a (fig. S7A).These data suggest a
model in which pDC-
derived IFN-a acts directly and indirectly viainduction of TNF
bymonocytes (with IL-18) toactivate MAIT cells in response to
ChAdOx1(fig. S9). To test thismodel in vivo, wild-type
(WT)C57BL/6J, Il18rap−/−, Ifnar−/−, and Tnfrsf1a−/−
Tnfrsf1b−/−micewere immunizedwithChAdOx1.MAIT cells from these
animals were thenanalyzed by RNA-seq (fig. S10, A and B, anddata S5
to S8). Principal components analysisidentified a strong gradient
of activation, whereMAIT cells from Ifnar−/− mice were mostsimilar
to those from naïve animals, and MAITcells from
Tnfrsf1a−/−Tnfrsf1b−/− and Il18rap−/−
mice had intermediate transcriptional profiles(Fig. 3, H and I).
The effector genes Cd69 (atboth the gene and protein level),
Cxcl10, Cxcl11,Ccl5, and Gzmb were all regulated along thisgradient
(fig. S10, C and D). Other genes (suchas Cxcl9) were only regulated
by TNF signaling(fig. S10D). In total, 51% of the genes induced
byvaccination were regulated by one or moreof these cytokine
pathways, and 11%were co-regulated by two or more of these
pathways(Fig. 3J and data S9). Thus, TNF, IL-18, andespecially type
I IFN play a critical role in vivoin Ad vector–induced MAIT cell
activation.Human volunteers showed a significant in-
crease in IFN-g–producing T cells after ChAdOx1boosting
immunization (Fig. 4A). The degree ofexpansion positively
correlated with MAIT cellactivation (Fig. 4B). To determine whether
thiswas a causal relationship, WT and Mr1−/− mice,
Provine et al., Science 371, 521–526 (2021) 29 January 2021 2 of
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A B
D E
C
F
G
H I
naïvenaïve
naïvenaïve
Fig. 1. Activation of human and murine MAIT cells by adenovirus
vectors. (A to C) Human PBMCs (n = 9donors; four experiments) were
stimulated with Ad5-GFP or ChAdOx1-GFP [multiplicity of infection
(MOI) = 0 to104 vp (viral particles)]. MAIT cell CD69 (A), granzyme
B (GzmB) (B), and IFN-g (C) expression was measuredafter 24 hours.
(D and E) Human PBMCs (n = 5 donors; two experiments) were
stimulated with the indicatedvectors (species in parentheses). MAIT
cell GzmB (D) or IFN-g (E) expression was measured after 24
hours.C, species C; non-C, non–species C. (F and G) C57BL/6J mice
(n = 6 mice per group; representative of twoexperiments) were
immunized intramuscularly (i.m.) with 108 IU (infectious units) of
Ad5-GFP or ChAdOx1-GFP.Inguinal lymph node (iLN) and liver MAIT
cell CD69 (F) and GzmB (G) expression was measured after24 hours.
(H and I) Healthy human volunteers (n = 14) were immunized with a 5
× 1010 vp dose of ChAdOx1MenB.1. (H) MAIT cell CD69 expression 1
day before and 1 day after immunization. (I) Pearson correlation
ofchange in plasma IFN-g levels after vaccination with the change
in MAIT cell CD69 expression. *P < 0.05; **P <0.01; ***P <
0.001. Unpaired t test [(A) to (C)], two-way analysis of variance
(ANOVA) [(D) and (E)], one-wayANOVA with Sidak correction for
multiple comparisons [(F) and (G)], or Wilcoxon rank-sum test (H).
Symbolsindicate average response [(A) to (C)] or individual mice or
volunteers [(D) to (I)]. Mean ± SEM is shown.
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which lack MAIT cells (16), were used (fig. S11, Ato C). After
vaccinationwith ChAdOx1 expressinganoptimizedhepatitis C virus
(HCV) antigen (17),Mr1−/− mice had significantly reduced
frequen-cies of HCV-specific CD8+ T cells compared withWT mice
(Fig. 4C and fig. S11D). No significantdefect in HCV-specific CD4+
T cells was observed(fig. S11E). We also observed defects in the
CD8+
T cell responses of Mr1−/− mice vaccinated withthe candidate
SARS-CoV-2 vaccine, ChAdOx1-
nCoV-19 (Fig. 4D and fig. S11F) (7). WT andMr1−/− mice were then
given a homologousChAd63-ovalbumin (OVA) prime-boost immu-nization
(fig. S11G) (18).Mr1−/−mice displayedreduced OVA-specific CD8+ T
cell responsesafter both priming and boosting (Fig. 4, E andF).
Differences in the microbiome (19) or gen-eral immunodeficiency
ofMr1−/−mice did notexplain these differences in
immunogenicity(fig. S12).
MAIT cells can sense the diversity of theAd vector–induced
innate immune activationlandscape (e.g., IFN-a, TNF, IL-18),
integrat-ing these signals to augment vaccine-inducedCD8+ T cell
immunity. The blend of signalsrequired to maximally trigger MAIT
cellsdescribed here includes a critical pathwayvia type I
IFN–dependent TNF release, relieson cross-talk between two distinct
popula-tions of transduced cells, and varies between
Provine et al., Science 371, 521–526 (2021) 29 January 2021 3 of
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Fig. 2. Activation of MAIT cells by adenovirus vectors requires
pDC-derivedIFN-a and monocyte-derived IL-18. (A and B) Gene
expression analysis ofMAIT cells isolated from the PBMCs of human
volunteers 1 day before and 1 dayafter vaccination with ChAdOx1
MenB.1 (n = 14 vacinees). (A) Volcano plot ofdifferentially
expressed genes [log2 fold change (FC) > 1, adjusted P <
0.05]. Thetop 10 up-regulated genes are annotated. (B) Selected
cytokine signalingpathways from the Reactome database enriched by
GSEA. NES, normalizedenrichment score. (C) Pearson correlation of
change in plasma IFN-a level aftervaccination with the change in
MAIT cell CD69 expression. (D) Overlap of genesup-regulated in MAIT
cells from ChAdOx1-vaccinated volunteers (“human in vivo”),from
human PBMCs stimulated with ChAdOx1 (“human in vitro”), and from
thedraining inguinal LNs of ChAdOx1-vaccinated mice (“mouse in
vivo”). (E and F)Human PBMCs were stimulated with ChAdOx1-GFP, and
the following inhibitorswere used: vaccinia virus–derived type I
IFN antagonist B18R (1 or 10 mg/ml;
n = 7 donors; three experiments) or anti-IFNAR2 antibody (10 or
25 mg/ml;n = 5 or 3 donors; two or one experiments, respectively)
(E); or anti-IL-12,anti-IL-15, or anti-IL-18 antibodies (10 mg/ml;
n = 5 donors; two experiments)(F). MAIT cell IFN-g expression was
measured after 24 hours. PBS, phosphate-buffered saline. (G and H)
PBMCs were depleted of CD123+ pDCs or leftuntreated and stimulated
with ChAdOx1-GFP. MAIT cell IFN-g expression(n = 8 donors; three
experiments) (G) or levels of IFN-a in the cell culturesupernatant
(n = 4 donors; one experiment) (H) were measured after 24 hours.(I
and J) PBMCs were depleted of CD14+ monocytes or left untreated
andstimulated with ChAdOx1-GFP. MAIT cell IFN-g expression (n = 4
donors; twoexperiments) (I) or IL-18 levels in the supernatant (n =
4 donors; three experiments)(J) were measured after 24 hours. *P
< 0.05; **P < 0.01; ***P < 0.001.Repeated-measures one-way
ANOVAwith Dunnett correction [(E) and (F)] or unpairedt test [(G)
to (J)]. Symbols indicate individual donors. Mean ± SEM is
shown.
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adenovirus serotypes. Our data, coupled withstudies in the lung
(4, 20, 21), support amodelthat places MAIT cells in a critical
bridgingposition between innate and adaptive immu-
nity. The mechanism by which MAIT cell ac-tivation promotes
antigen-specific CD8+ T cellresponses remains to be defined.
However,local production of chemokine CXCL10 repre-
sents a promising candidate as it can promoteCD8+ T cell priming
(22).It is notable that the activation of MAIT
cells is tightly linked to the immunogenicity
Provine et al., Science 371, 521–526 (2021) 29 January 2021 4 of
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Fig. 3. IFN-a acts directly and indirectly through the induction
of TNF toactivate MAIT cells. (A) Human PBMCs or purified CD8+ T
cells (n = 3 donors;one experiment) were stimulated with the
indicated cytokines (50 ng/ml). MAITcell IFN-g expression was
measured after 24 hours. (B) Purified CD8+ T cells withor without
CD14+ monocytes (n = 4 donors; one experiment) were stimulatedwith
IFN-a and IL-18 (50 ng/ml). MAIT cell IFN-g expression was measured
after24 hours. (C) Purified monocytes (n = 3 donors; one
experiment) werestimulated with IFN-a (50 ng/ml) or left untreated.
After 24 hours, supernatantswere transferred with or without IL-18
(50 ng/ml) to autologous purified CD8+
T cells. MAIT cell IFN-g expression was measured after 24 hours.
(D) TNFproduction by IFN-a–treated CD14-purified monocytes was
measured after24 hours (n = 3 donors; one experiment). (E) Purified
CD8+ T cells (n = 10 donors;four experiments) were stimulated with
IFN-a and IL-18 with or without TNF(50 ng/ml) or anti-TNFR2 agonist
antibody (2.5 mg/ml). MAIT cell IFN-g expressionwas measured after
24 hours. (F) PBMCs were stimulated with ChAdOx1, and thefollowing
inhibitors were added: vedolizumab (anti-a4b7 integrin antibody, n
= 8donors; two experiments), adalimumab (anti-TNF antibody, n = 11
donors; three
experiments), or etanercept (TNFR2-Fc fusion protein, n = 8
donors; two experiments)(10 mg/ml). MAIT cell IFN-g expression was
measured after 24 hours. (G) PBMCswith or without CD14 depletion
were stimulated with ChAdOx1. Concentrationof TNF in the
supernatant was measured after 24 hours (n = 4 donors;
oneexperiment). (H to J) C57BL/6J (n = 4), Il18rap−/− (n = 3),
Tnfrsf1a−/−Tnfrsf1b−/−
(n = 4), or Ifnar−/− (n = 4) mice were immunized i.m. with 108
IU of ChAdOx1-GFP.Naïve C57BL/6J mice (n = 4) were used as a
control. After 24 hours, MAITcells were isolated from the iLNs and
sorted for RNA-seq (one experiment). (H)Principal components
analysis. (I) Heatmap of the up-regulated differentiallyexpressed
genes (log2 FC > 1, adjusted P < 0.05) between MAIT cells
fromChAdOx1-immunized and naïve C57BL/6J mice, with all other
groups shown forcomparison. (J) Overlap of the genes up-regulated
(log2 FC > 1, adjusted P < 0.05)in MAIT cells from
ChAdOx1-immunized and naïve C57BL/6J mice, and the
genesup-regulated in MAIT cells from ChAdOx1-immunized C57BL/6J
mice as comparedto each of the ChAdOx1-immunized knockout strains.
*P < 0.05; **P < 0.01.Unpaired t test [(B), (C), and (G)],
repeated-measures one-way ANOVA with Dunnettcorrection [(E) and
(F)]. Symbols indicate individual donors. Mean ± SEM is shown.
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of adenovirus vectors. This technology hasemerged as a potent
platform for T cellimmunogenicity in clinical trials for HIV(23)
and as vaccines for emerging virusessuch as Ebola (6) and
SARS-CoV-2 (7, 8).This knowledge can be harnessed to improvethe
design of these vaccines against majorpathogens and cancers.
REFERENCES AND NOTES
1. N. M. Provine, P. Klenerman, Annu. Rev. Immunol. 38,
203–228(2020).
2. L. Loh et al., Proc. Natl. Acad. Sci. U.S.A. 113,
10133–10138(2016).
3. B. van Wilgenburg et al., Nat. Commun. 7, 11653 (2016).4. B.
van Wilgenburg et al., Nat. Commun. 9, 4706 (2018).5. A. Vitelli et
al., Expert Rev. Vaccines 16, 1241–1252 (2017).6. European
Medicines Agency, New vaccine for prevention of
Ebola virus disease recommended for approval in theEuropean
Union, press release (29 May 2020);
www.ema.europa.eu/en/documents/press-release/new-vaccine-prevention-ebola-virus-disease-recommended-approval-european-union_en.pdf.
7. P. M. Folegatti et al., Lancet 396, 467–478 (2020).8. F.-C.
Zhu et al., Lancet 396, 479–488 (2020).9. K. M. Quinn et al., J.
Clin. Invest. 125, 1129–1146 (2015).10. J. E. Teigler, M. J.
Iampietro, D. H. Barouch, J. Virol. 86,
9590–9598 (2012).11. M. J. Johnson et al., J. Immunol. 188,
6109–6118 (2012).12. A. Subramanian et al., Proc. Natl. Acad. Sci.
U.S.A. 102,
15545–15550 (2005).
13. S. A. Samarajiwa, S. Forster, K. Auchettl, P. J.
Hertzog,Nucleic Acids Res. 37 (suppl. 1), D852–D857 (2009).
14. V. Hornung et al., Nat. Immunol. 9, 847–856 (2008).
15. L. C. Garner, P. Klenerman, N. M. Provine, Front. Immunol.
9,1478 (2018).
16. E. Treiner et al., Nature 422, 164–169 (2003).
17. T. Donnison et al., Vaccine 38, 5036–5048 (2020).
18. A. Gola et al., Sci. Transl. Med. 10, eaap9128 (2018).19. A.
Varelias et al., J. Clin. Invest. 128, 1919–1936 (2018).20. A.
Meierovics, W.-J. C. Yankelevich, S. C. Cowley,
Proc. Natl. Acad. Sci. U.S.A. 110, E3119–E3128 (2013).21. A. I.
Meierovics, S. C. Cowley, J. Exp. Med. 213, 2793–2809
(2016).22. V. Peperzak et al., J. Immunol. 191, 3025–3036
(2013).
23. D. H. Barouch et al., Lancet 392, 232–243 (2018).
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Fig. 4. Impact of MAIT cell deficiency onT cell responses after
ChAdOx1 or ChAd63immunization. (A) Frequency of
IFN-g–producingPBMCs measured by peptide enzyme-linkedimmunospot
(ELISPOT) in ChAdOx1 MenB.1 vacci-nated volunteers before boost (n
= 14) orday 14 after boost (n = 13). SFU, spot formingunits. (B)
Spearman rank correlation analysis ofthe change in MAIT cell CD69
expression frombefore boost to day 1 after boost versus theincrease
in IFN-g–producing PBMCs from beforeboost to day 14 after boost.
(C) C57BL/6J (n = 12)or Mr1−/− (n = 9) mice were immunized i.m.
with108 IU of ChAdOx1-HCV-GT1-6_D_TM-Ii+L (twoexperiments). On day
16, HCV-specific CD107a+,IFN-g+, TNF+, or IFN-g+TNF+ CD8+ T cell
responseswere measured. (D) C57BL/6J (n = 12) or Mr1−/−
(n = 11) mice were immunized i.m. with 108 IU ofChAdOx1-nCoV-19
(two experiments). On day 13,SARS-CoV-2 spike-specific CD107a+,
IFN-g+, TNF+,or IFN-g+TNF+ CD8+ T cell responses weremeasured. (E
and F) C57BL/6J (n = 12) orMr1−/− (n = 12, n = 11 after boost) were
primed i.m.with 107 IU of ChAd63-OVA and boosted intra-venously on
day 28 with 108 IU (squares) or 109 IU(circles) of ChAd63-OVA.
SIINFEKL-specificCD107a+, IFN-g+, TNF+, or IFN-g+TNF+ CD8+ T
cellresponses were measured either 3 weeks afterprime (E) or 3
weeks after boost (F). *P < 0.05;**P < 0.01; ***P < 0.001.
Wilcoxon rank-sum test(A) or two-way ANOVA [(C) to (F)].
Symbolsindicate individual volunteers or mice. Mean ± SEMis
shown.
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ACKNOWLEDGMENTSWe thank H. Ferry and L. Hardy for assistance
with cell sorting;S. Slevin, C.-P. Hackstein, and C. Willberg for
critical discussions;M. Salio and V. Cerundolo for the Mr1−/− mice;
J. Rehwinkelfor the Ifnar−/− mice; M. Esposito, H. Al-Mossawi, L.
Ni Lee, andT. Donnison for reagents; the NIH Tetramer Facility for
the MR1tetramers; and all of the volunteers for sample donation
andparticipation in the trial. Funding: N.M.P. is supported by
anOxford-UCB Postdoctoral Fellowship. A.A. is supported by
aWellcome Clinical Training Fellowship (216417/Z/19/Z). L.C.G.
issupported by a Wellcome PhD Studentship (109028/Z/15/Z).M.E.B.F.
is supported by an Oxford-Celgene Doctoral Fellowship.S.B.M. and
T.S.C.H. are supported by the Wellcome Trust (211050/Z/18/Z and
211050/Z/18/A). E.B. is supported by the MedicalResearch Council
(STOP-HCV and MR/R014485/1), an NIHR SeniorFellowship, the NIHR
Biomedical Research Centre (Oxford), andthe UKRI/NIHR through the
UK Coronavirus ImmunologyConsortium (UK-CIC). C.S.R. is supported
by the NIHR BiomedicalResearch Centre and is a Jenner Institute
Investigator. A.J.P. is
supported by the NIHR Oxford Biomedical Research Centre and isan
NIHR Senior Investigator. P.K. is supported by the WellcomeTrust
(WT109965MA), the NIHR Biomedical Research Centre(Oxford), the
UKRI/NIHR through the UK Coronavirus ImmunologyConsortium (UK-CIC),
and an NIHR Senior Fellowship. TheChAdOx1 MenB.1 clinical trial is
funded by the Medical ResearchCouncil DPFS (MRM0076931). The views
expressed are those ofthe authors and not necessarily those of the
NHS, the NIHR, or theDepartment of Health. Author contributions:
N.M.P. and P.K.designed the project. N.M.P., A.J.S., C.D.,
T.S.C.H., E.B., C.S.R.,A.J.P., and P.K. designed the experiments.
N.M.P., A.A., L.C.G.,A.J.S., C.D., C.H., L.S.R., M.E.B.F., M.U.,
H.S., and S.B.M.performed the experiments. S.C., B.O., M.R., F.T.,
T.L., S.C., A.F.,E.B., C.S.R., and A.J.P. provided samples and
reagents. Allauthors contributed to the writing and editing of the
manuscript.Competing interests: C.D., C.S.R., and A.J.P. are
namedinventors on a patent application in the field of
meningococcalvaccines. A.J.P. waives his rights under any patent.
P.K. is anamed inventor on a patent application in the field of
cancer
vaccines. Data and materials availability: All gene
expressiondata are deposited in the Gene Expression Omnibus
underGSE158835. All data are available in the manuscript or
thesupplementary materials.
SUPPLEMENTARY MATERIALS
science.sciencemag.org/content/371/6528/521/suppl/DC1Materials
and MethodsFigs. S1 to S12Tables S1 and S2
References (24–44)
MDAR Reproducibility Checklist
Data S1 to S9
View/request a protocol for this paper from Bio-protocol.
1 May 2019; resubmitted 20 July 2020Accepted 19 November
202010.1126/science.aax8819
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MAIT cell activation augments adenovirus vector vaccine
immunogenicity
Christine S. Rollier, Andrew J. Pollard and Paul
KlenermanSharpe, Sophie B. Morgan, Timothy S. C. Hinks, Teresa
Lambe, Stefania Capone, Antonella Folgori, Eleanor Barnes,Michael
E. B. FitzPatrick, Senthil Chinnakannan, Blanche Oguti, Meriel
Raymond, Marta Ulaszewska, Fulvia Troise, Hannah Nicholas M.
Provine, Ali Amini, Lucy C. Garner, Alexandra J. Spencer, Christina
Dold, Claire Hutchings, Laura Silva Reyes,
DOI: 10.1126/science.aax8819 (6528), 521-526.371Science
, this issue p. 521; see also p. 460Sciencebe exploited to
enhance the efficacy of vaccines.
T cell immunity to target antigens after vaccination. This work
suggests an additional pathway that could+impaired CD8positively
correlated with vaccine-mediated T cell responses in human
subjects, and mice deficient in MAIT cells showedplasmacytoid
dendritic cells as well as monocyte-derived interleukin-18 and
tumor necrosis factor. MAIT cell activation
produced byαimmunized mice (see the Perspective by Juno and
O'Connor). This activation required interferon- report that a
leading adenoviral vector vaccine, ChAdOx1, activated MAIT cells
inet al.context of viral infections. Provine
recognize derivatives of microbiota-derived vitamin B2
precursors but can also be activated by certain cytokines in the
Mucosal-associated invariant T (MAIT) cells are a T cell subset
important for mucosal homeostasis. These cells
Vaccines get a help-MAIT
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REFERENCES
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