Jam'nai.{iii ”mmmplume
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`63..
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`VOLUME 194, NUMBER it FEBRUARY 1, 2015 ' WWW.JIMMUNOL.ORG
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`g
`PROPERTY OFTH
`"Mum NATIONAL
`mm LIBRARY OF
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`Genome & Co. v. Univ. of Chicago
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`PGR201 9- 00002
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`UNIV. CHICAGO EX. 2021
`
`

`

`Immunology
`
`Table of Contents
`
`j't-wJournal of
`
`VOL 194 I NC). 3 | February I, 20l5 | Pages 84.54386
`
`IN THIS ISSUE
`
`845 Driving CARS over the Threshold See article ,0. 9} 1
`Finding Friends for AIRE See rtrtr'ct't' p. 92;’
`Thymocyte Peer Pressure See rtrtrrt'r p. 1'05?
`One More Reason To Take Your Vitamins See rtrtic't'r p. [090
`The Skin-ny on Secondary Lymphoid Organs in Transplantation Set: article ,0. I364
`
`Pl LLARS OF IMMUNOLOGY
`
`847 Laying Bare the Node Mouse Gene
`(tmtmm Andi-ism: and Nicholas 1’. McClrn-tiy
`
`849
`
`Pillars Article: New Member of the Winged-Helix Protein Family Disrupted ln Mouse And Rat Nude
`Mutations. Nature. 1994. 372: 103-107
`Mit'brrt’i. Neitt't. Dir-tartar {754 err. Michael Shimmy. Harts Hedrirfi. aim" 735mg“; BN5,”
`
`BRIEF REVIEWS
`
`855 The Acute Respiratory Distress Syndrome: From Mechanism to 'lit'anslation
`.‘ilr'mtgHye Hm: and Roma K. Mrn’irtmprtt’li
`
`CUTTING EDGE
`
`863 Cutting Edge: Maresin—l Engages Regulatory T Cells To Limit Type 2 innate Lymphoid Cell Activation
`and Promote Resolution of Lung Inflammation
`Nrtrtdi'rtt Kronor/trimming Prrtrfoi R. Barrett. jewrmtd Drtt't'i. Rafa—1:15: if. (id‘dtttiflmtl', Romain (faint
`Ridge-51’ P. Phipps, Nico: A. Proofs, Myrna K. Kat-trivia.
`(Litre-tr: N, Sci-Imp, mm" 3m“. D. [my
`
`’i'erqm'ir Rants”
`
`868 Cutting Edge: Critical Role For (ISaRs in the Development of Septic Lymphopenia in Mice
`jrtittitrm y". (finder, Hatteras}; [‘irtttrtr‘ii. Nitrite! K. Dick, Firm 8. Zrtwmr. and Peter A. Wrote“
`
`873
`
`(Cutting Edge: AIM2 and Endosomal TLRS Differentially Regulate Arthritis and Aut
`in DNase ll—Deficient Mice
`’
`t’r’rt‘zt’o‘rt 3mm, Sbrtrti .S‘hrrririrt.
`.‘a'ttrriir (.‘rrrpmtr-r. Qtrmt-th’tf it, Pan-rm}: 3mm,
`firm Mrmfmi—Retflstrm, and Hit-it M,
`(Emirrrt't'm’
`
`‘
`t'b
`,,
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`om ' my I “‘dllCtlon
`[Quinn-3m» A Fitzgerald
`I,
`
`On the cover: Motility of the infective larval stage of the intestinal l‘telmintb Hefflqrrtrtmrtioin’rs pohigyrttt t’mii’rh; sh
`.
`'
`in temporal color code {120 frames. ()0 seconds). Raiser-volt Bicren. l.. B. Volpe. M. Kulagin. [1b. Sutherland PW?"
`A. Stir?" 3- .l» Mélr-‘il‘l'l‘l- l S. Vt’l'bCL‘k- and N- L.
`l'ial‘l‘is. ZOIS. Anobody-mediated trapping of ltelminth l‘irv- ’-
`I'lllu‘
`
`|54-—l I63.|I‘M:Cl)l lb and Fc'y receptor 1.}. torrential “L "(WINS ‘
`
`
`
`
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`
`'
`I'
`iliitr‘ tritium! ry‘firtmtmrtl'ogv (ISSN 0022—1767) is published twice each month by The American Association
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`Inc” 9650 Ruckville Pike. Bethesda. MD 20814—3994. Phone: 301—634—7197. Fax: 301—634-7829 9u[vac-rit:tiriiintiiiiiiliniilm‘
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`Copyright (C) 2015 by The Atomic:
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`878
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`883
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`887
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`898
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`9|]
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`LJ71
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`9 2‘)
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`940
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`950
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`960
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`973
`
`Cutting I'iLIgL‘: Epigenetic Regulation of Harp} Delines :1 Stable Population oI'CD—i' Regulatory T Cells
`in 'I'ttmors from Mice and Humans
`
`jer'ruti’ H. Weight. Shirt}? Mimi. Bo Martyr. ({tmzbrmg Qi'J-t. Kramer}! IV. Hittite. Dung Xflrtitg. Raina? Night: You but.
`Kiri-tiling Lo, Heir» barber-mo. Robert Hrgfirieirrer, (mt/f Nit-brim; 5', Wife”:
`
`Cutting Edge: Progesterone Directly Upregulal'es Vitamin l) Receptor Cene Expression for Eliieient
`Regulation of T Cells by (ialcitriol
`.Wirtmlm- Hemgmimui.
`fllfyuglrrm Kim I’mmgritin .‘irm. Xi'm‘iir {benign {It-(jam Kim. fee H.
`Regime!” Ninth.
`I 1m" 15. Bro.\'mtf_wi'. (ma! (.I’mng H. Kim
`
`[.ee. _,a'r.rirg}w.rm (film,
`
`ALLERGY AND OTHER HYPERSENSITIVITIES
`
`II.-l() and Regulatory T Cells Cooperate in Allergen—Specific Immunothemp}r 'I’o Ameliorate
`Allergic Asthma
`Mm}: Hiiiflm. jam-Mm Mrtt‘eiuer.
`Hour-fart: .‘tir‘hifd. Hfgrir fit-Intuit.
`
`l'r‘el'eri fl-ftjwr—fi/r'rrm'ri. between: Newer. Stimm Hutton. Alumina; ft't'l’iti.
`i’iii’u'rrs R‘W“ and (Reform: 1;»me
`
`ANTIGEN RECOGNITION AN D RESPONSES
`
`Fixed Expression oI‘SingIe Influenza Virus—Specific 'I‘( R Chains Demonstrates the Capacity For
`‘I'CR 0t— and B—Chain Diversity in the Face of Peptide—M HC Class I Specificity
`If. Bridle (.i’It’mr'HS. Peter (I. Hubert)». Nita/e L, hr (from, {Hid .H'tryn’ieirf.
`i’io'irer
`
`'I‘argel Antigen Density Coverns the Eliicacy ofAnti—CI)2li—CDZ8—CI)3 g Chimeric Antigen
`Receptor—Modified Effector CDS' T Cells
`Kristie:- Wirrrmmbe. Setter-n Yemeni-a. Auto» (3. Mai-rm.“ hm: mm Met-rim. bio-1mm Urhfmmrt. Mira bani.
`Remit: summit. Timmmi‘i (Erato. Rim Harrtay'i'ri'. Nubttfifil'rt
`IIHHUIM'SI’HI.
`lt’rrz.r{}rml'i
`.‘a'bimridrt. fibrin}?! Whiz/rim.
`i-h‘mhi Kfrm'. Yi'rsrrye Niriu‘dra Hamil-f Name. and Mml’om Mmum
`
`AUTOIMMUNITY
`
`Honieodomain—Interaeting Protein Kinase 2. a Novel Autoimmune Regulator Inter-action Partner.
`Modulates Promiscuous Gene Expression in Medttllary ’l‘hymic Epithelial Cells
`Kristin Rumor. firm'ue (,ilmm'r’, Enron? Rt'z‘rwrfnfifjt, fiery}: Mam. ”rooms ff. Hrgfiitrrmt. Bram: ltjt’ttrrkf.
`xmdfl'm Drrt'n'mkr
`
`CLINICAL AND HUMAN IMMUNOLOGY
`
`The V (.iene Repertoires o|"(i]assicaI anti Atypical Memory B Cells in Malaria-Suseeptible West
`African Children
`
`.S'et’eri‘u Ziirr‘inli't'r. (Routine f5. Sir‘i’u‘mfler. “Itfiitbili’f'h'm'f'. new Hogarth, Miriam? W/arirfirig. firm-Nicolas Sr‘lu'rl'r‘l.
`{frit- fi-frfli'r.
`interim Karenina. ABM-‘1’“ {)itgrii'lirr. Brutflhft‘fll'
`i’i'mirti‘ and .‘s‘rrrrrii K. Pierre
`
`Differential IixpreSsion olithe ‘I'ranscription Factor ARII)3:I in Lupus Patient Hematopoietic
`Progenitor Cells
`t'I'iUt'J'trfle 1., Ratliff: j'nfie M. me'. jam: '2". Wheat”. ftm’irfi A. fauna. and Elvira." I".
`
`IIi’t'fn":
`
`Combination ‘I'herapy with Anti—CTLA—4 and Anti—PD—I Leads to Distinct Immunologic
`Changes In Vivo
`Rinrprrriinr i'thi'. Rahal; Verona flit/trio 521m". (bandit: .S't'il'hrrr Briddiiprrfli. Sm” N.
`Harriet Ringer. fifttigrtret (.ierJ'Mir. fetid I). WWIV’WI'. Rm}: Hrrl'ebmr. Mediate V.
`mid Kmart: M.
`[JIIIWJKIIJI'PJI’I‘H'
`
`(i'r’rtfitger.
`t'MmfrrpII'm'.
`
`Club—Mediated Induction of ECRZ and II.-1{l as Potential Regulatory Mechanism for Cl)2(:
`Cost‘ilnttl:1tol‘}-' Pathway
`Rite Harem, Ker {)birtrmrr. Her-trim (thmlw. rant” It’tmriyrt. {Noni i’iul’f.
`Kn ()Ii'mmrrrr. our! (.Iifi’rm rI’fm'r'umm
`
`.Sittwlu' hmm. New H.
`
`[.Lmlt‘n
`
`Sterile Ill“ Rearrangements Reveal that Distance Between (iene Segments on the Human lg H Chain
`Locus Inl-Iuences 'I'heir Ability 'I'o Rearrange
`NM Plunger”?! Harriett. Audra-s Mam/{jet}: Latter. mm’ Nit-{mt Harrington
`
`

`

`983
`
`090
`
`t)9 9
`
`1011
`
`I021
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`[031
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`103‘)
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`I 047
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`1057
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`1062
`
`I 06‘)
`
`1080
`
`IMMUNE REGULATION
`
`Immune Complexes Suppress IFN—y—Imlucetl Responses in Monocytes hy Activating Discrete Members
`oli the SRC. Kinase Family
`(i'iiiiiiiri' ii.
`ilat’iI-iiriari'r. Aiiiia (i. Mt'fr‘rai‘ii. ji'iiiiifer i". A. Sit-idea: aim" (ferairi M. H'iiiiiiaii
`
`Modulating DNA Methylation in Aetivated (IDBI ’1' Cells Inhibits Regulatory ‘1' (Iell—[mluced Binding
`of lioxpfi to the CD8+ T Cell
`IL—Z Promoter
`Midwife M. Miiii’i’. Nat-mm Ham-mitt, fiiiziriiirrii M. Yi’ieiiipsaii.
`
`i'iigit‘
`
`.fiyi’aia 1".
`
`i'r‘arm’. aiirifiiiiariiaii if.
`
`Efflctor '1' Cells Boost Regulatory '1" Cell Expansion Is): 11:2. INF, 0X40. and Plasmaeytoid Dendritie (Tells
`Depending on the Immune Context
`.‘ifliv‘e (ii'tigiiire. Bram: Zai'agaza.
`Aiirii'iy Barfiri‘iir. David Saaa'ami.
`i‘i’tifiit‘m'ir' Miami. Aiigt‘iiiit' Raiien‘.
`I'i'iiilii’i (ii'iiifieig—b'iijvei'. (iii/e5 Marciriaii.
`tliiiflfit' Piaget?» arid h'i'iiiiii i.. baitiiiiaii
`
`Intestinal Helminths Regulate Lethal Acute Graft—vetsus-Host Disease and Preserve the (Iral't-versus—Iumor
`Effect in Mice
`
`iiaiiii. Aiiriiwf Meiiiiaii. fastylli 1'". Urban, fr;
`i'l’iiciiar‘i Henry. (Irii‘iaii N.
`I’iie ii. iiiiiig—t'iii (.iiii'ii, Nadine Baiiiiicie,
`Paiii 8.
`itai‘iiiiiaii. Garage}. Wriiiar. Brace R. Biazai‘. Datiid if. Hiiari. aiia’ M. Nediiii hire
`
`Chronic Morphine-Induced MicroRNA-124 Prontotes Microglial Immuttosttppression by Modulating
`P65 and 'IiRAFG
`
`Siiiiiui'i Qiii. I’iiiiiii i‘it'iig. (ieiie image.
`
`I’i‘iig Xiiaiig, diaries Sinai-i,
`
`i.i'i' He. 1'? H. Yi' (.iriim’ii’.
`
`I'iiig i’eiig. aim’ I Jr'iiiig I'iii
`
`Survival 01‘ Human Circulating Antigen-Induced Plasma Cells 15 Supported by Plasma Cell~Niche
`Cytokines and T Follicular Helper Lymphocytes
`Iliiii Riiiaw—Aiiirgiii, Hearriz Radi‘ikiiez—Baymia, Riibéii LéPt'Z‘B/rfflt'o, Haiti: zliidiijar. [Viallft‘rf I’iii'i‘a—Aii’gi'e,
`rlriiaiiia (Pannier—Carri, aririjast; /I. Briana
`
`‘I‘empotal Expression oI‘Gtowth Factors Triggered by Iipiregulin Regulates Inflammation Development
`Mantra Harada. Dairmlie mlnlinl'l'fi'rf. Yasiriiiiiiii Ariiiia, Hirasi'Ji Kriiiiall'a. Yiy'i Nakamqi, Minivan Niriiiali.
`'iiii‘ri Arrriiiii.
`fie Mr’iig. Hideiiari' Hairdo. Rafter: .‘ii'iigii. iaii'ariiiya .‘iiriiiiiai‘iiiai. fling-jinx jiaag. Nai‘ikii it'iiiiiai. Naiiiivml'i fl’iirasail'a.
`.Saiiiii‘a Sakada. KaiiI'a I‘Iriaiaia‘iii-‘iiiaiiiam. Hideiei ()gm'a.
`ihsiii'a i-i'i'i'aim. and Masaall'i Miiraaaiiii
`t
`.
`
`CD401. induces Functional 'I'unneling Nanotuhe Networks Exclusively in Dendritic Cells Programmed
`by Mediators of Type I Immunity
`it’aiiairif. Feet-k. Aai‘iilia i..
`(.‘fliit‘rrii it. Katmai. Simaii Cf. Watkins, Paitiri it'aiiiirii'i,
`Veipaiidi Avjraaoa, Cliiai‘i’er R. Riiiaida. aim’ Rabbir B. KI-iaiiiiaivi
`
`I’aier. Rim??? i).
`
`.S'aiii’i‘.
`
`IMMUNE SYSTEM DEVELOPMENT
`
`Stable Interactions and Sustained 'I‘CR Signaling Characterize ThymocyteJI'Itymocyte IttteraCIions that
`Support Negative Selection
`Heather}. Meii'r'iiai', Jimmy 1’). Ross. kayt’eigii i:
`
`iayiai'. rim! Jillian A. Rainy
`
`IMMUNOG EN ETICS
`
`The Human 11:23 Receptor rsI 1209026 A Allele Promotes the Expression of a Soluble 11,—23R-Iincoding
`mRNA Species
`Raviiiaim'
`I". Ya, itairiiiiriir iii-await. and (firm! (iiil'iagiri'i'
`
`IMMUNOTHERAPY AN D VACCIN ES
`
`Induction of Potent (IDS '1' Cell Cytotoxicity 11y Specific 'I‘argeting of" Antigen to Cross-Presenting
`Dentlritic Cells In Vivo via Murine or Human XCRI
`
`it'iii’irii i'iai'iiiiig. Mariiiia Becker. Aiiiiaiii’ii Hai'ireia, Neit- liege. Aiiiil’a fr'i‘il'r'l'. Andreas .Iti'iiiilijfl.~ Hairiia' Il'i’ebai'.
`(J'ii‘ii'irifii; Weiii’. (Haiti/iii (iieret'il’e. Vaiat'i' Hemi.
`.SZrepiiiiiiii’ Crimea. itbimaiiiiiiar AiMrias‘s‘iar/ir.
`infirm W. Magrs.
`aiia’ it’ir‘iiai'ri A. Kris-moi?
`
`(IDH '1‘ (Iell ‘I'olerance to a 'I'untor-Associated Selt—Antigen 1s Reversed by (3174 '1' Cells Engineered
`'I'o lixpress the Same ‘1' Cell Receptor
`Sara (iiiai‘asiiiaii,
`i’r'rii'a Veiig‘ii. igiiiiiiiir (Jiiiii. fliiiie-Marii' fl-ft‘Nii'oi. Hr'ii (.lrii'peiiri'r. rliigr'iika Heifer. ifiiiiiia Nieiiailmii.
`Mailjvaiii fliiiiiarii. Mathias Xei'ii. Shari—Air Xian IV/riifléaiig Ui'ai'i'r. it'iiiiiia Mam}. Rriiijaii (J'ia 'J‘iH-Ti‘fli. and Ham}. .‘i'iaiirs
`
`

`

`1090
`
`I 101}
`
`1112
`
`1122
`
`1131
`
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`1154
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`1164
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`116‘)
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`1178
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`I 191}
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`l l‘)‘)
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`1211
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`122“)
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`INFECTIOUS DISEASE AND HOST RESPONSE
`
`I‘he tit—'I‘oeoplterol Form oli Vitamin Ii Reverses Age—Associated Susceptibility to .S‘myinn‘m‘rm pnennmnine
`Lung Infection 11y Modulating Pulmonary Neutropltil Recruitment
`iz‘irn N. Him (iinrnnn. .‘imrir (Ennis Xirmgnng iJn. Urrynng Wit. Andrew ( .inniiii. faint ii i. Lt’Wflg. nnri .‘s‘iniin N. A-l'errinni
`
`A Maior Role lot Myeloid—Derived Suppressor Cells and a Minor Role For Regulatory T Cells in
`IInmunosuppression during Srrrpnyinmrmr {HH‘E'II‘S Infection
`Christina ikinrrrz. Stern}; Anirn Harri,
`'i'in; .Spnmnmer. Jim-Mn Hnr’iin. Andreas Beineiee. (icing Peru's. nnri EM Medinn
`
`Atg7 Enhances Host Defense against Infection via Downregulation of Superoxide but Upregulatiott of
`Nitric Oxide
`
`ij‘i'ng U.
`
`l’nn l’e. Xiri'nn Zimn. (.‘nnlnin Hnnng. and Min Wit
`
`IRAK4 as a Molecular Target in the Amelioration ol‘ Innate lmmunityFRelaretI Iindotoxic Shock and
`Acute Liver Injury by Chlorogenic Acid
`5m: Hung Park, smug—n linen, jienn Ynn, Setmgmin ire. iJn Vining l’non. fire—itjirrrigjnng. Sting-Him jnng,
`Bring Venn Hnning. fin inc Hang,
`.SIII’UI'X'HHF Hnn, rind I'nnngmn Kim
`
`Diverse Roles for T—l)et in the Effector Responses Required For Resistance to lnfletion
`(i-ft‘fi‘lif’fi ”(trim Pritt‘inn'd. Aiding f) Hnrn Hid}, David fl.
`(i'in'isrinn.
`.S'ngir’ Wrigngr’. an Hing. (thin Mnniir’ni.
`Hymn jnim. Arieiie (finrtnnn Annuity. Wiiiinm (i. Dnnn, jm'nm’iine i’errrgane, Smut-n 1.. Rainer.
`and Christopher fl. Hnnn'r
`
`'1' Cells Complement Antibodies in Protecting against Yellow Fever Virus
`(2138'
`Mnrin ii. Bnrri, Micinn’i Knngtgnnrti. Mnn'n A. Snfi’nren, (inrii'rinn i‘r'figt’l'. Mirhnri Rm'nnmm. Knmr’n .‘a’iejndr.
`Bernie Hnsen, Anette Shy/1n. Srn‘en Brim, fan i’. Un'isremrn, rind Aiinn R. ”Janina:
`
`Antibody—Mediated Trapping of Helmintlt Larvae Requires CDI lb and [icy Receptor I
`faint finer-non Bierm. Bentrirr Wipe, Manner? Krdngin. Duncan .8.
`.S'nrbenflrmd,
`it’tmmin (inirt‘. Arne .S'rjrz,
`Herginmin f. Mar-timid, ]. yefl/erbern. and Nimin‘ L Harris
`
`Complement Component (:5 Recruits Neutropltils in the Absence of C3 during Respiratory Infection
`with Modified Vaccinia Virus Ankara
`
`i’ijiiip j. R. Price, Znirén Bénki, Angeiili’n .S'rln‘izirirr. Heriin-rr Steiner. Adnnn' Verm’mar, (1}er finite-r.
`mm" Mirbnei H. idnnnnn
`
`INNATE IMMUNITY AND INFLAMMATION
`
`'I‘RIF—Ikpendent Innate Immune Activation Is Critical for Survival to Neonatal Gram—Negative Sepsis
`Mex (i. (Tin-not. Diriinr N. joiner. Ltn'i F. (it’miie, Angein L (inc-nor. from L. Wynn. Kindnr M. Keiiy-Smnipin.
`Philip 0. Srnmpin. Kevin [5. fie/fins. I’ijiiip A.
`ij‘i'nn, Dinn Ndeionniej. (Jinn inf. Shannon M. Winn-i. Weider H. Reeves.
`Cfirrrrnn if. Minnow. and Lyle L Moidntwr
`
`Radiation Exposure Induces lnHammasonte Pathway Activation in Immune Cells
`Veir M, .‘imecniein. Akinm‘i Until-n.
`.S‘bizn h'bfli’dflh’i. rlfirdeiine R.
`indexer. Lorenz WérritI-z-Jriiinei’. nnrijnnn’: x'l. Leaflet?!”
`
`'IILRZ Modulates Antibodies Required For Intestinal IsehemiaiReperl‘usion—Induced Damage and
`Inflammation
`
`Mirinrei R.
`
`i’npr- nnri Sherry D. Firming
`
`A Second Stimulus Required for Enhanced Antilimgal Activity ofthiman Neutrophils in Blood ls Provided
`by Anaphylatoxin (33a
`Kerstin Hiinnigrr. Kristin Biebrr. Ronny Martin.
`Nieit C. iiim’ernnnn, nnri Oiiner Knrzni
`
`i’i-resrr Lennnrr. Mitre Yiiiin i‘igge. finger; Irwin. Rm—Feng (inn.
`
`Neutrophil Priming Occurs in a Sequential Manner and Can Be Visualized in Living Animals by Monitoring
`11,—] [3 Promoter Activation
`Vi
`l’n‘o.
`iflmnm‘i Aitirrnrin'nin. fennifir A. Obtain. .S‘inni (ieng. Rnn in. .rtnri Akin:
`
`iinl'ntiiinni
`
`Zehrafish [RFI Regulates II‘N Antiviral Response through Binding to II-iNthI and IFNdJfi Promoters
`DUWI‘ISIFCRI‘I‘I of Myl')88 Signaling
`Hni Feng. Yi—Bing Xining. Qi—Min lining. Kiri U. Qi— I}: ”bring. nndfinn—ang (ini
`
`

`

`135‘} Milt-12? Modulates Macrophage Polarization anti l’rolnotes Lung lnllatnmation antl lniury lty Activating,
`the _]NK Pathway
`iimigjir ling. I’rmimii Kong. Hang Xinmg. {Jimgiitt Kim". jingymi Xi”. Kile in. Hmim’mau Wong.
`
`i’r'iig NH. and Limo; Kiri
`
`1252
`
`Protective Role for Caspase-II during Acute Experimental Murine Colitis
`it”:t:‘i:erim’ I”. Sirt'i'irrm.
`it'mmzyim Ufitjm’ltiert. fiitlfiiiirie Ran-'i'riiemr. (iriin'ieiid r'It-'i:'iiti. Siriiiilim (i. Wirtrie. rim! ”icing“.
`Sitimd (3. (km: Home W. Kati.
`iJril’e x1. O'Neiii. Kingston H. (i.
`rl’l'iiis. :mri ifiiiimi M.
`(.‘rr'rigir
`
`I261 Apoptosis—Assoeiatetl Speck—like Protein Containing a CARI) I‘orms Specks- hut Does Not Activate
`Caspase—I
`in the Absence of NLR1‘3 during Macrophage Swelling
`Vincent (Joaquin. Fatima: i‘r'iirr!iii—.S':ii-n'i:ez, Iliim‘tr: it’rirajri-Mrrzn. {firm}: [ripen-(.irsnjrin. Am i, Gomez.
`Air'xei I’enl'irmtsky. omit Brniigh. and Pubic: i’eirgrin
`
`1274 Endogenous Intracellular Catltelieidin Enhances TLR‘) Activation in Dentlritic Cells and Macrophages
`Yiti’itmim Ngikdgmm mid Richard 1..
`(Milli;
`
`1285 Complement Deficiency Promotes Cutaneous Wound Healing in Mice
`Stavros it’afitii.
`imimiis it’nm'rzeiis. Periil’iir (i. Furriers. Mirt‘itj M. Miti'al’im'si'i. Robert A.
`Danie! Rit‘il'iin.
`iiiizgiizeri: /1. (iriei'. :rmijahii i}. Lzmibri;
`
`th'KIHgt'iia'. Mam fitnu'ieiitm
`
`1292 The Endoplasmic Reticulum Adaptor Protein IiRAdP Initiates NK Cell Activation via the Ultcl 3—Met1iated
`NF-KB Pathway
`in” (Jim. Lu i'iim. (.‘iirmg Li. Briefing l’-.
`i’eifi’iig ii.
`l’img iimi. HRH" Krista: Frm
`
`I’iiig Du. Hoiigiirm Xitrriig. Ha Long, Piugpiug Kim. Henry Lin.
`
`i.ifliih‘ Hing.
`
`I304 Distinct Cellular SourCes oi" Hepoxiliu A] and Leukotriene 8., Are Used To Coordinate Bacterial—Induced
`Neutrophil 'I'ransepithelial Migration
`fl'iii'imei A. Patent. W’obeeii i’irzui. Mei M. Yankee. (.‘itrismpbe i'l’im'ii'tmrr. Ken's-‘9” (frown. rmri Ben!” 11".
`
`i'h-‘J‘iijlr
`
`1316 Knockdown of [lie Antiapoptotic Bel-'2 Family Member AliBH—I Protects Mice from Anaphylaxis
`iz'iemwm Uttimi. Maurine Igimrg.
`i'l’l'ujrr Stii'itrriskri. Andrew I’iiiririger. imri (imumr i’. Nibtm:
`
`MOLECULAR AND STRUCTURAL IMMUNOLOGY
`
`I323 Pltospltatidyliuositol 4-I’Itospltate 5-—Kinase 0t and Vayl Mutual Cooperation in CDZB—h-letliatetl Actin
`Remodeling and Signaling Functions
`Michell: Mutt-Mini. Cristina (.iriiipi‘ria. Nii‘ia i’rn‘eieiiu.
`Rit‘t‘iiirriri (iriimiririui. :mri {mt-mi
`'i'imsm
`
`.S‘iimma Christi. Cristina (.irtpmmn. Amma‘iirr 1-1pm.
`
`MUCOSAL IMMUNOLOGY
`
`I334
`
`11.—2RB—-Dependent Signaling and CD103 Functionally Cooperate ‘I'o Maintain 'I‘oleranee in the Cut
`Mueosa
`.
`Xirmmei Yuri”. Mirimr‘i j. Dee. Norman H. Aitmrm. and 'lijwims R.
`
`il’i'ait'rl'
`
`TRANSPLANTATION
`
`134?
`
`lliN-y Production lty Memory Helper "1' Cells Is Required For C1)4I]-lI‘ILIL'pCIILIt'I‘Il Alloantilmtly Responses
`Victoria (inrimriir'm. Rd}! iim. Xi Wang. Wiiiiriiit M. Baldwin, Hi. Robert L Fairt'iriiri. :mii (1mm Vitittisl'il’ir
`
`1337 Attti-lL—Ili'23 p40 Antibody Attenuates Experimental (.iltronic (ir:1Ft-ve|'stts—Host Disease via Suppression
`of lIiN-yillxl 7—Producing Cells
`.S'tieiiipn Ukrmwm. Hirimki {5:55:me Hitrtil’rtzrr Niririmm-i. Km-iriji Maintain. Nnimimrrr iitiiii. Hist-i Mimi".
`'l'inl’eitim 'iiriirtil’rt. Aeiijii’o Ym'bimm'ri. Mitsmte 'iimimnm. and Ytisiiiimbu Mamie
`
`1.564 Both Reiectiou and ‘I'olerance oii Allografts Can Occur in the Absence of Secondary lymphoid 'liissues
`(.irtrir i). hum.
`lin'biiiribii Alaiyrmiri. Kartsmmri ‘iimml’a'. Simm Sheri. Yoiiei I’mmtiiri, Semi; E. (.‘mnmiiy. jute Merino,
`George:
`i‘mrr'a. imd (iiiiet Beiiit‘iirm
`
`NOVEL IMMU NOLOGICAL METHODS
`
`13??
`
`'l'fill“ I'ixpression: Analysis with a Xstireeu ISLP Reporter Mouse
`(.‘eiirit' Hermit, Xi (.itr'u.
`'ii'isiiyit Hewitt.
`iii'i’fljtortiiiir. jay Lima”. Mark C Uriey, Stephen F.
`ihtiiiei F. Stat-demon. iiimei i‘i’igeubimm. iii} Kim.
`ir’J'
`ll”"iiiirmi.t. rim? W’i/iimu if.
`i’md
`
`i’m‘t'ri/ri.
`
`

`

`LETTERS OF RETRACTION
`
`138] Rcrraction: Ciuunosinu Inhibits (21340 Receptor Expression and Function Induced by Cymkincs and B
`Amyiuid in Mouse Microglia Cells
`.S'njfmm A'flim'mm'. M'irbi‘l I”. Ruth/Mum. .S'hin'nffirmg,
`fofmm’r.‘ D Hi’imimn’. Vim‘mzr; Nari. Elma Yimimo.
`Pmrizid I)! Emir). me‘i‘n‘v (ku'irrgfl. mid Ii’mrlm (firi'nnlfli
`
`CORRECTION 5
`
`I382 Corn-Gian: Rulc of Ncurrupllils in lL-l7—Dcpcndcnr immunity to Muwszll Candidiusis
`Amm R. Happier. Heather R.
`(,‘rmri, Midim'it .r’{minimicz-S'rmmx. Hui Um-m'flr'. Pam’m 3'. mums. and .‘n'm‘m’J L. {Ixy'flw
`
`1583 Cmrecrion: AID-Initiated DNA Lea-inns Arc Differentially I’roccsscd in Distinct B Cell Populations
`Khrmngo (Jim. SIR-it'd Haugrrmm’i. Summer 5. Virfinnfi'iitim‘i. Mnxmrfl' I). filer. Ximmu' (.‘I‘Jm. Mmrr: 3’: Has.
`.S'Jhmzoug me. Brim Human. arm’fing H.
`IMrmg
`
`1384 AUTHOR INDEX
`
`

`

`The Journal of Immunologyr
`
`
`'
`'
`.c as
`This material may be protected by Copvrtgbt law (Tltle 17u.s
`o
`
`
`
`)
`
`Combination Therapy with Anti—C
`TLA-4 and Anti—PD-l
`Leads to Distinct Immunologic Changes In Vivo
`
`Rituparna Das,*‘T Rakesh Vet-marl”F Mario Sznol,*’l Chandra Sekhar Boddupalli.*‘l
`Scott N. Gettinger,"“+ Harriet Kluger,*'+ Margaret Callahan} .ledd D. Wolchokji'
`Ruth Halaban,§ Madhav v. Dhodaprtarae' and Kavita M. Dhodapkar’k'l'l
`Combination therapy concurrently targeting I’D-l and C'l‘l.A-4 immune checkpoints leads to re
`though both HM and CPL/L4dampen the Tcell activation, the
`.
`in vivo effects of these dr
`To better understand biologic eii'ects of therapy. we analyzed bloodltumor tlss
`.
`immune checkpoint blockade. We show that blockade of (.T'l‘lA ,
`functional signatures in vivo in purified human '1‘ cells and monocytcs 'l‘hcrapydnduced changes are m
`in monocytes and involve largely nonoverlappingchanges in coding genes, Including alternativel}r
`ore prominent in T cells Illa“
`RNAs. Pathway analysis revealed that C’I‘LA-4 blockade induce '
`.
`'
`.
`spliced transcripts and noncodmg
`s a prolii'erative signature
`memory '1‘ cells. whereas I’D-l blockade instead leads to changes In genes Implreated |
`predominantly in a subset of tl‘aflsnialfi'I
`blockade leads to nonoverlapping changes in gene expression. including proliferationmsm
`n Cylolytsis and NK cell function. Conrlrinalm“
`apies also have differential effects on plasma levels of CXCIJII, soluble Ila-2R, and [[1
`rciated and chenlokine genes. These ther-
`following anti—PIN therapy may be incomplete in the tumor T cells even in the
`-lor. Importantly, I’D-l receptor (it‘t‘l'l’amf'v
`circulating T cells. These data demonstrate that. despite shared property of check
`setting of complete receptor occupancy ':
`alone. or in combination have distinct immunologic effects in vivo. Improved unders
`point blockade, Abs against rte-1. (.‘TM'
`agents in patients will support rational development of immune-based combinations
`landing of pharmaeodynamic effects of the“
`2015, [94: 950—959.
`against cancer. The Journal of inrrnnnolofls
`
`markable antitumor effect!“ M.
`
`ntigcn—spccilie T cell activation is regrrlated by a balance
`ot‘coslimulatory and coinhibitory signals. such as those
`mediated by inhibitory receptors C‘TLA—4 and PD-I {l}.
`Abs that block these inhibitory receptors or their ligands such as
`PDLJ have led to impressive antiturnor ell‘ects in several cancers
`(2. 3). ("ILA—4 blockade with lpilimurnah (Ycrvoy: Bristol—Myers
`Squibb. Princeton. NJ) was the lirst
`treatment demonstrated to
`improve survival of patients with stage IV melanoma In ran—
`domized trials (4). Clinical
`trials with anti—PD-l Ab (such as
`Nivolumab) have demonstrated promising clinical activity in di-
`verse tumor typcs. including melanoma. renal cell carcinoma. and
`lung cancer (5—8].
`In preclinical models. combined blockade of
`both I’D-l and (‘TLA—4 led to greater anlitumor effects than either
`Iherapy alone. and.
`in a recent clinical trial.
`the combination of
`Nivolumab and lpilirnunrab led to a distinct pattern of antitumor
`
`‘Departnlcnt of Medicine. Yale University School ol' Medicine.
`New Haven. ("I'
`”(1520:
`'Sinilow (.‘anccr (‘c
`'
`
`"'nc. New Haven.
`{'l‘ ”(1520.
`.
`Ior (‘ancer lnrmunorlrerapy, Meinor'i
`zrl Sloan Kettering
`(‘tiocer t‘cnter. New York. NY lilllofi: Illlepzlrtlnenl ol‘llerrrratology. Yale University
`School of Medicine. New Haven. ("I' ”(153”: and ‘Dcpnrllllt‘ltl of Pediatrics. Yale
`University School of Medicine. New Haven. ("1' rroszo
`Received lor publication Jilly ‘1 7
`This work was supported in part by National Irrslitut ‘.
`r'ro K.M.l}.i. ('AltlotttlE rlo M.\«".I).J. (‘AIJISI It] {to MAUI}. KE-it'nli-‘Elli ilo lib].
`and I’Slivt'r‘r I2 I974 (Io K”. and KMJM and the Dana Foundation and Hyundai Hope
`on Wheels r‘ro KMJM.
`Address corresisandcnce and reprint requests to Dr. Krrvira M.
`I'Jhorlapkar. Yale
`University School of Medicine. .133 (‘cdar Street. New Haven. ('1' ”(1320.
`li-nrail
`address: kavita.dhrnhrpkar(rr'yulerrlu
`'l'hc onlinc version of ihrs article contains supplcmclilrll rmrlcrlai.
`Abbreviations used in this article: [‘rarnlio. combination; Set]. sequential.
`('rmyrighl -'r
`1- ElliS by The American Aswcialion ol'irrrnrunologisrs. Inc. rrnz— Ilium3525 till
`
`wwwjinInIunol.org.lcgii'doilI[1.-lllllii’iiurnruuol.l-llllbiso
`
`aclivity. With rapid and deep tumor regressions in a substantial
`proportion of melanoma patients {9. 10).
`Clinical studies of PD—l and (‘TLA-4 blockade in cancel
`patients have shown that the two therapies have clear differences
`in ”3“ frequency illld pattern of immune—related adverse event!»
`l3.
`lll- Whereas the preclinical models of l’D—l or CTl-‘A‘J.
`blockade have to date been poorly predictive ol' the Film“ Oi
`immune-related adverse events observed in the clinic. gentillt
`deletion oi" PD—l or (.‘TLA-4 leads to very different effect-‘4 "1
`mice. C‘Tl.A—4 knockout mice suffer from a lethal lyllll’h‘mm
`lil'erative disease. whereas deficiency of PHI leads to IcS-‘i We“:
`phenotype with slrain—specilic autoimmunity {IE—lo). Allhoutlh
`both I’D—l and ("ILA-4 act
`to dampen T cell activation “'3
`shared signaling Pathways. dil‘l‘crcnccs in sites ol‘ action have.
`been proposed to help understand the dil‘l'erences in patterns 01
`autoimmunity as well as antitunror effects with PD—l and (‘TLA'
`4 blockade. For example. the effects o|‘("l‘L/-\~4 may be mostly
`in lymphoid Iissue. whereas l’D-l
`iirteraerions may primilrlly
`occur in the periphery. Inhibitory signaling via both PIN and
`.
`.
`.
`II
`("HA—4 in human T cells in cultnr
`C Willi shown It) L‘tJIIVngl’ t)
`certain nodes such as inhibition ol‘ Akl plrosphorylation. aI'
`tlrorrgh the proximate events may dil'l‘cr. such as the involrcmcllt
`ol' phosphatase Pl’2A with ("ILA-4. but not PD-l (IT—1")- “"'
`proved understanding ol' the ch
`anges in gene expression “1 Vim
`in humans using gcnorrre—widc
`approaches in specific intuit-Inc
`cells in response to checkpoint blockade therapy may in'dc
`‘
`-
`'
`c
`new insights into the mechanisms ol'
`antlttllttol' and tlllltllll'lil‘llln
`ei‘l'ects with these
`agents.
`In parlicular.
`it
`is important
`to an:
`dcrstand whether combination checkpoint blockade in Vivo leillli‘
`to distinct or synergistic biologic eti‘ccts compared with block-
`rule of individual checkpoints in humans,
`
`

`

`'l he Journal of Immunology
`
`Materials and Methods
`Patients
`
`lilood and tumor tissue was obtained from patients [ti = 45}
`lacrlllllct‘al
`“”‘ICTgUlnt! inmulne checkpoint hloekade after obtaining informed consent
`under a separate protocol for the collection of research samplesapproved
`ll)“ 1'10 Yale University institutional Review Bound. This included patients
`receiving anti-PU-l
`in = 24}. anli—(."l‘l.:\-¢l
`ttt : '4}. or combination
`{{‘U'l‘bui therapy ti: = IE: ‘1! concurrent. 3 sequential |Ser.||}.
`
`Cl)” "'"t'tttt'rttirut .fitt' gene erpt‘esstritt ttttttt'lt‘s't's'
`
`l’BMII's were ohtained by density gradient centrifttgation pretext. using
`l‘llL‘Ull I’atple Plus t('ili l-lealth (‘arc Life Sciences}. Monocytes were sorted
`from l’lth"s using anti—human (‘DH microl'neads tMiltcnyi liiotect using
`
`the nrauul'acturer‘s protocol t2tt}. Sample separation was performedusing
`
`MACS-LS columns tMiltcnyi Biotcct. Tire (”Bl-l
`l'r: ‘tion “’4'” lU'Tl‘L‘f
`
`Hllhljected lo rt second round of separation for T cells
`sing llurnarl Pm:
`T Cell Isolation Kit
`| tMiiteuyi Bioteci. Purity of sorted populatiot‘ts W‘“
`tttonitot'ed by flow cylomelry tSupplemental Fig. Ml. MWWY'C" “ll‘l
`l' cells ohtained by MACS head separation were pelleted. suspended in
`Riff litrller tQiagenJ. and stoned at
`-8l)"(' for RNA isolatlon.
`
`Gm" "lit-"Pitt's”: analyst's rtfttut't'ltert’ ttmttrttjt'tes' out! i' r'elis
`RNA was extracted from puritied ntonocyles and T cells uriintl ll“: RNL‘il-‘Y
`Mini kit
`from Qiagcn. We employed Al't‘ynretris (teneft'hrp Human
`franscriptorne 1U microarrays for gene expression prolilrng to allow
`""“lY-‘iis ol'coding as well as noncoding and alternatively spliced tranfit‘fll’l-‘iv
`Palm" Pmlltcritpy altrl postthcrapy samples from each patient Ior each CL'll
`li'l‘te [mourn-Vic or 1' mini.) were compared directly to evaluate tlrcr'apy-
`induced changes. We used (icncspring {1X llfi platform to :tnillFV-t'
`ll":-
`L‘hanges in L'tllllllg genes. exnn workltow ot’tltc ’al1elt US (it) Ioanalyze tlte
`alternatively spliccdesons 1t] genechip. as described by Whistler et al. l; l.
`22]. and l’artcL US as platform to analyze changes in the nnnL‘IHlllLL‘
`genes.
`
`All‘lll'a‘t's of coding genes
`
`Dilltl [II] Clllllllg genes WL'I'L‘ analyzed using (lCIICSPI'lIlg (5X llj |Jlillillrlli
`lzlli- Data were imported via eson espr'cssion workllnw ctnl'tlt‘lllnil
`EMA”! or Pl..ll£Rlo tnormalizationi for analyzing the eodiltg genes using
`the specilie :mnolation support tile for human transcriptrnue array 3.“ (as
`lirovided hv (lettespring (iXt. Experiment grouping for each treatment
`cohort
`ranf'...p])_] alone. anti—("I‘LA—«l alone. concurrent amt Pl)-| +
`E“llII-("l‘lflaxun (‘ornho and PD—l following ("HA—4‘. Seq] was created for
`lll‘lll T cells and monocytcs. alrd interpretation for
`the posttrealnrenl
`compared with pretreatment samples was generated.Quality control
`f'llitlysis was used in principal component analysis and lor probe hybrid,
`Ization intensiitcx For the irlentiticalion of the differentially regulated
`Coding genes herween post- and pretreatment samples for all
`treatment
`groups under eaclt cell type. the locus lilter Was set on codmg only genes
`ll'l'l‘A gene chip 2.” covers 44,699 genestn‘anscripl clusters}. We Itt'tltllt'sl
`ll
`' “N With a In value cutoff set at “.05. followed by th‘ Ullfilll’L‘W'SF‘l
`Cltlsluring analvsis using (lenespring clustering workllow tliuclldean tits—
`”litre metric arid Ward's linkage rule 1. Further statistical analysis involved
`“l‘hlication ot' a fold—change threshold of L}; differentially regulated genes
`Wt‘ll‘ then manually curated ln incltrde coding gettes only.
`.>
`.
`3' rttiru'ctr analysts
`Pathway analysis ofdit'i'ercntially expressed genes was pctlllr'm'd “5'"9 ll“:
`,L‘lal‘ul'c pathway analysis platt’ornl
`t2tlt.
`|)it'fr.‘rt.‘llliztll}I
`I'CEL'lmCd 11'5““
`llh'lfi with p ‘1' [1.05 and fold change of L | .3 were used from each‘trcaltilt‘ltt
`gm”I“ as input
`for the Metacorc pathway platl'omt. and ditierentralljr
`I"Jill'léllcd pathways maps and gene ontology terms were generated-
`
`“l Hairs-rir of attritionI let}: split ‘m' scar-V
`Anilli'sis to detect the potentially alternatively spliced genes was pet'lia'med
`”‘illg the lison workllow of the ‘artck (55 (Lo hy taking into account exnn
`
`“miles from Al'fvmelris ”To 2.0 genccltip. as described by Whistler cl til.
`IE]. 22}. “Kilns-“fill: a p value -':.ll.tl:‘r were included for analysis. We oh-
`luilted number of exon pmhc sets in caclt
`transcript cluster twitlt corre-
`guarding transcript cluster identification derived from the nreta-prohe set
`lllet and discarded clusters with "Hill prohe sets or "
`Ill prone scts and
`
`Included eson clusters will] ttll'splil't.‘ p value -
`'tt.tit}t}til. The list of alter-
`"tltively spliced genes was tiltercd on gene clusters with p values -' llllfi and
`a fold change of” _t_
`t
`..’I hetween pr-ethcrapy and posttlterapy samples to oh.
`
`tain splice variants that wen.
`Ilso dil'terentially regulated at the gette level.
`
`“)3 l
`
`iittttl'lt‘sis' trfttortr'rtrlt‘ttg genes
`
`li'oranalyring the noucoding data. we used the ’ar'lelt' US (1.0. postimporting
`data. and we employed the tiller on noncoding genomic loci 02.829} to
`retain only the nonctxting probe sets on the ”TA 2.0 genechip from all
`samples. Statistical analysis involved one-way ANNA. followed by ap—
`plication oi'a fold change threshold of [J to generate nrmcmling transcript
`lists {unadjusted}: value. tittfii. All the noncoding prolic setsttranscript lists
`were further curated manually tvia University of California Santa Cruz.
`linsemhl}. Venn diagr'a rs were generated between dill'erent
`treatment
`groups under each cell type.
`
`Quantitative FUR
`
`RNA from T cells isolated from patients pretherapy and posttherapy was
`used to validate the ruicroarray data for the expression of Kim and ICOS by
`quantitative.
`|’(‘R using the assays on demand primer prohes tAppIied
`iiioseieneesi. [Expression of UM’IJII was monitored as a housekeeping
`gene, Reactions were set up in triplicates using li'f.
`I’C‘R L‘ore reagents‘
`{Applied Bioscicnccsl. according to manufacturer‘s protocol. Relative
`espressiou of target genes was calculated using co