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Antigen Presenting B Cells Facilitate CD4 T Cell Cooperation Resulting in Enhanced Generation of Effector and Memory CD4 T Cells.doc

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Antigen Presenting B Cells Facilitate CD4 T Cell Cooperation Resulting in Enhanced Generation of Effector and Memory CD4 T Cells

AntigenPresentingBCellsFacilitateCD4TCell CooperationResultinginEnhancedGenerationof EffectorandMemoryCD4TCells DavidR.Kroeger¤a,ChristopherD.Rudulier¤b,PeterA.Bretscher* DepartmentofMicrobiologyandImmunology,UniversityofSaskatchewan,Saskatoon,Saskatchewan,Canada Abstract Weshowthattheinvivogenerationofcytokine-producingCD4Tcellsspecificforagivenmajorhistocompatibilityclass-II (MHCII)-bindingpeptideofhenegglysozyme(HEL)isfacilitatedwhenmiceareimmunizedwithsplenicantigenpresenting cells (APC) pulsed with this HEL peptide and another peptide that binds a different MHCII molecule. This enhanced generationofpeptide-specificeffectorCD4TcellsrequiresthatthesamesplenicAPCbepulsedwithbothpeptides.Pulsed Bcells,butnotpulseddendriticcells(DCs),canmediateCD4Tcellcooperation,whichcanbeblockedbydisruptingOX40- OX40L(CD134-CD252)interactions.Inaddition,thegenerationofHELpeptide-specificCD4Tcellmemoryisgreaterwhen miceareprimedwithBcellspulsedwiththetwopeptidesthanwithBcellspulsedwiththeHEL-peptidealone.Basedon ourfindings,wesuggestCD4Tcellcooperationisimportantforvaccinedesign,underliesthephenomenonof‘‘epitope- spreading’’ seen in autoimmunity, and that the efficacy of B cell-depletion in the treatment of human cell-mediated autoimmune disease is due to the abrogation of the interactions between autoimmune CD4 T cells that facilitates their activation. Citation:KroegerDR,RudulierCD,BretscherPA(2013)AntigenPresentingBCellsFacilitateCD4TCellCooperationResultinginEnhancedGenerationofEffector andMemoryCD4TCells.PLoSONE8(10):e77346.doi:10.1371/journal.pone.0077346 Editor:PadraicG.Fallon,TrinityCollegeDublin,Ireland ReceivedJune17,2013;AcceptedSeptember4,2013;PublishedOctober14,2013 Copyright: ? 2013 Kroeger etal. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited. Funding:ThisworkwassupportedbyaNaturalSciencesandEngi