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Susan L Swain - One of the best experts on this subject based on the ideXlab platform.
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age associaTed increase in lifespan of Naive cd4 T Cells conTribuTes To T Cell homeosTasis buT faciliTaTes developmenT of funcTional defecTs
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Hirotake Tsukamoto, Karen Clisedwyer, Gail E Huston, Debra K Duso, Amanda L Buck, Lawrence L Johnson, Laura Haynes, Susan L SwainAbstract:WiTh age, T-Cell generaTion from The Thymus is much reduced, yeT a subsTanTial Naive T-Cell pool is mainTained even in aged animals, suggesTing ThaT Naive T Cells eiTher persisT longer or Turn over fasTer To mainTain T-Cell homeosTasis. We found ThaT wiTh age, Naive CD4 T Cells became progressively longer-lived. Their longer lifespan did noT depend on recogniTion of self-pepTide/class II. Newly generaTed Naive T Cells derived from aged sTem Cells had a shorTer lifespan, like ThaT of young Naive T Cells. Conversely, Naive CD4 T Cells derived from middle-aged ThymecTomized mice were longer-lived in vivo, and Their developmenT of funcTional defecTs was acceleraTed. These observaTions suggesT ThaT Naive T Cells develop Their longer lifespan during Their sojourn in The periphery. Increased longeviTy of Naive CD4 T Cells correlaTed well wiTh reduced expression of proapopToTic molecule Bim. We suggesT ThaT The inTrinsic increase in longeviTy helps mainTain Naive T-Cell homeosTasis buT faciliTaTes The developmenT of funcTional defecTs in mice.
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cd4 T Cell memory derived from young Naive Cells funcTions well inTo old age buT memory generaTed from aged Naive Cells funcTions poorly
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Laura Haynes, Sheri M Eaton, Eve M Burns, Troy D Randall, Susan L SwainAbstract:Age-relaTed declines in immune funcTion have an impacT on boTh primary and memory responses. In This sTudy, we have examined The abiliTy of Naive CD4 T Cells from young and aged T Cell recepTor Transgenic mice To esTablish funcTional memory. We found ThaT memory Cells generaTed from young CD4 T Cells responded well To anTigen, even a year afTer generaTion, whereas memory Cells derived from CD4 T Cells from aged mice responded poorly boTh ex vivo and in vivo. Memory Cells generaTed from aged Naive Cells proliferaTe less, produce reduced levels of cyTokines, and exhibiT reduced cognaTe helper funcTion, compared wiTh memory Cells generaTed by using young Naive Cells. These resulTs indicaTe ThaT iT is The age of The Naive T Cell when iT firsT encounTers anTigen, raTher Than The age when iT reencounTers anTigen, ThaT is criTical for good memory CD4 T Cell funcTion.
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cosTimulaTory requiremenTs of Naive cd4 T Cells icam 1 or b7 1 can cosTimulaTe Naive cd4 T Cell acTivaTion buT boTh are required for opTimum response
Journal of Immunology, 1995Co-Authors: Caroline Dubey, Michael Croft, Susan L SwainAbstract:EfficienT iniTiaTion of a CD4 T Cell response requires boTh acTivaTion Through The TCR and cosTimulaTion provided by molecules on APC wiTh counTerrecepTors on The T Cell. We invesTigaTed The relaTive conTribuTion of The ICAM-1:LFA-1 and B7:CD28/CTLA-4 cosTimulaTory paThways in Naive T Cell acTivaTion, using eiTher anTi-CD28 Ab or fibroblasT Cell lines TransfecTed wiTh I-Ek, which express eiTher no cosTimulaTory molecules, ICAM-1 alone, B7-1 alone, or ICAM-1 and B7-1 TogeTher. PepTide Ag or immobilized anTi-CD3 was used To provide The TCR signal. CD4 T Cells from mice Transgenic for The V beTa 3/V alpha 11 TCR, which recognize a pepTide of pigeon cyTochrome c complexed To I-Ek, were used as a source of Naive T Cells. Naive T Cells sTimulaTed wiTh Ag or anTi-CD3 responded well To high numbers of APC expressing eiTher ICAM-1 alone or B7-1 alone. However, APC expressing boTh ICAM-1 and B7-1 were much beTTer sTimulaTors of proliferaTion and IL-2 secreTion aT low Cell numbers, and were far superior inducers of IL-2 aT higher numbers, indicaTing a synergy beTween The Two paThways. STimulaTion provided by ICAM-1 could noT be solely aTTribuTed To adhesive sTrengThening of oTher paThways, since cosTimulaTion was seen when immobilized anTi-CD3 was used and when ICAM-1 only APC were added, indicaTing ThaT ICAM-1 was in facT acTing as a classic cosTimulaTory molecule. BoTh The magniTude of The response and The amounT of cosTimulaTion required for response were dependenT on The inTensiTy of TCR inTeracTion. These resulTs suggesT ThaT an efficienT Naive T Cell response requires boTh a sTrong TCR signal and more Than one cosTimulaTory signal ThaT will synergize wiTh The TCR signal. This offers an explanaTion as To why APC such as dendriTic Cells and acTivaTed B Cells, which express high levels of mulTiple cosTimulaTory/adhesion molecules, are The only APC ThaT eliciT Naive T Cell responses.
Thomas Schuler - One of the best experts on this subject based on the ideXlab platform.
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il 7 derived from lymph node fibroblasTic reTicular Cells is dispensable for Naive T Cell homeosTasis buT crucial for cenTral memory T Cell survival
European Journal of Immunology, 2020Co-Authors: Laura Knop, Katrin Deiser, Ute Bank, Amelie Witte, Juliane Mohr, Lars Philipsen, Hans Jorg Fehling, Andreas Muller, Ulrich Kalinke, Thomas SchulerAbstract:: The survival of peripheral T Cells is dependenT on Their access To peripheral LNs (pLNs) and sTimulaTion by IL-7. In pLNs fibroblasTic reTicular Cells (FRCs) and lymphaTic endoThelial Cells (LECs) produce IL-7 suggesTing Their conTribuTion To The IL-7-dependenT survival of T Cells. However, IL-7 producTion is deTecTable in mulTiple organs and is noT resTricTed To pLNs. This raises The quesTion wheTher pLN-derived IL-7 is required for The mainTenance of peripheral T Cell homeosTasis. Here, we show ThaT numbers of Naive T Cells (TN ) remain unaffecTed in pLNs and spleen of mice lacking Il7 gene acTiviTy in pLN FRCs, LECs, or boTh. In conTrasT, frequencies of cenTral memory T Cells (TCM ) are reduced in FRC-specific IL-7 KO mice. Thus, sTeady sTaTe IL-7 producTion by pLN FRCs is criTical for The mainTenance of TCM , buT noT TN , indicaTing ThaT boTh T Cell subseTs colonize differenT ecological niches in vivo.
James J Moon - One of the best experts on this subject based on the ideXlab platform.
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response To commenT on The role of Naive T Cell precursor frequency and recruiTmenT in dicTaTing immune response magniTude
Journal of Immunology, 2013Co-Authors: Marc K Jenkins, James J MoonAbstract:Our Brief Review focused on recenT sTudies ThaT used pepTide:MHC TeTramer-based Cell enrichmenT To explore The role of Naive T Cell precursor frequency in dicTaTing immune response magniTude To foreign Ags. Thus, our lisT of Naive T Cell frequencies for foreign epiTopes only included resulTs from
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The role of Naive T Cell precursor frequency and recruiTmenT in dicTaTing immune response magniTude
Journal of Immunology, 2012Co-Authors: Marc K Jenkins, James J MoonAbstract:RecenT advances in Technology have led To The realizaTion ThaT The populaTions of Naive T Cells specific for differenT foreign pepTide:MHC (p:MHC) ligands vary in size. This variabiliTy is due, in parT, To The facT ThaT cerTain pepTides conTain amino acids ThaT engage in parTicularly favorable inTeracTions wiTh TCRs. In addiTion, deleTion of clones wiTh cross-reacTiviTy for self-p:MHC ligands may reduce The size of some Naive populaTions. In many cases, The magniTude of The immune response To individual p:MHC epiTopes correlaTes wiTh The size of The corresponding Naive populaTions. However, This simple relaTionship may be complicaTed by variabiliTy in The efficiency of T Cell recruiTmenT inTo The immune response. The knowledge ThaT Naive populaTion size can predicT immune response magniTude may creaTe opporTuniTies for producTion of more effecTive subuniT vaccines.
Janko Nikolichžugich - One of the best experts on this subject based on the ideXlab platform.
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Two separaTe defecTs affecTing True Naive or virTual memory T Cell precursors combine To reduce Naive T Cell responses wiTh aging
Journal of Immunology, 2014Co-Authors: Kristin R Renkema, Gang Li, Angela Wu, Megan J Smithey, Janko NikolichžugichAbstract:Naive T Cell responses are eroded wiTh aging. We and oThers have recenTly shown ThaT unimmunized old mice lose ≥70% of Ag-specific CD8 T Cell precursors and ThaT many of The remaining precursors acquire a virTual (cenTral) memory (VM; CD44hiCD62Lhi) phenoType. In This sTudy, we demonsTraTe ThaT unimmunized TCR Transgenic (TCRTg) mice also undergo massive VM conversion wiTh age, exhibiTing rapid effecTor funcTion upon boTh TCR and cyTokine Triggering. Age-relaTed VM conversion in TCRTg mice direcTly depended on replacemenT of The original TCRTg specificiTy by endogenous TCRα rearrangemenTs, indicaTing ThaT TCR signals musT be criTical in VM conversion. ImporTanTly, we found ThaT VM conversion had adverse funcTional effecTs in boTh old wild-Type and old TCRTg mice; ThaT is, old VM, buT noT old True Naive, T Cells exhibiTed blunTed TCR-mediaTed, buT noT IL-15–mediaTed, proliferaTion. This selecTive proliferaTive senescence correlaTed wiTh increased apopTosis in old VM Cells in response To pepTide, buT decreased apopTosis in response To homeosTaTic cyTokines IL-7 and IL-15. Our resulTs idenTify TCR as The key facTor in differenTial mainTenance and funcTion of Ag-specific precursors in unimmunized mice wiTh aging, and They demonsTraTe ThaT Two separaTe age-relaTed defecTs—drasTic reducTion in True Naive T Cell precursors and impaired proliferaTive capaciTy of Their VM cousins—combine To reduce Naive T Cell responses wiTh aging.
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lifelong persisTenT viral infecTion alTers The Naive T Cell pool impairing cd8 T Cell immuniTy in laTe life
Journal of Immunology, 2012Co-Authors: Megan J Smithey, Vanessa Venturi, Miles P Davenport, Janko NikolichžugichAbstract:PersisTenT CMV infecTion has been associaTed wiTh immune senescence. To address The causal impacT of lifelong persisTenT viral infecTion on immune homeosTasis and defense, we infecTed young mice sysTemically wiTh HSV-1, murine CMV, or boTh viruses and sTudied Their T Cell homeosTasis and funcTion. Herpesvirus + mice exhibiTed increased all-cause morTaliTy compared wiTh conTrols. Upon LisTeria- OVA infecTion, 23-mo-old animals ThaT had experienced lifelong herpesvirus infecTions showed impaired bacTerial conTrol and CD8 T Cell funcTion, along wiTh disTincT alTeraTions in The T Cell reperToire boTh before and afTer LisTeria challenge, compared wiTh age-maTched, herpesvirus-free conTrols. Herpesvirus infecTion was associaTed wiTh reduced Naive CD8 T Cell precursors above The loss aTTribuTable To aging. Moreover, The OVA-specific CD8 T Cell reperToire recruiTed afTer LisTeria challenge was enTirely nonoverlapping beTween conTrol and herpesvirus + mice. To our knowledge, This sTudy for The firsT Time causally links lifelong herpesvirus infecTion To all-cause morTaliTy in mice and To disTurbances in The T Cell reperToire, which Themselves correspond To impaired immuniTy To a new infecTion in aging.
Marcia A Blackman - One of the best experts on this subject based on the ideXlab platform.
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clonal expansions and loss of recepTor diversiTy in The Naive cd8 T Cell reperToire of aged mice
Journal of Immunology, 2009Co-Authors: Mushtaq Ahmed, Lawrence L Johnson, Kathleen G Lanzer, Eric J Yager, Pamela S Adams, Marcia A BlackmanAbstract:There are well-characTerized age-relaTed changes in The peripheral reperToire of CD8 T Cells characTerized by reducTions in The raTio of Naive:memory T Cells and The developmenT of large clonal expansions in The memory pool. In addiTion, The TCR reperToire of Naive T Cells is reduced wiTh aging. Because a diverse reperToire of Naive T Cells is essenTial for a vigorous response To new infecTions and vaccinaTions, There is much inTeresT in undersTanding The mechanisms responsible for declining reperToire diversiTy. IT has been proposed ThaT one reason for declining reperToire diversiTy in The Naive T Cell pool is an increasing dependence on homeosTaTic proliferaTion in The absence of new Thymic emigranTs for mainTenance of The Naive peripheral pool. In This sTudy, we have analyzed The Naive CD8 T Cell reperToire in young and aged mice by DNA specTraType and sequence analysis. Our daTa show ThaT Naive T Cells from aged mice have perTurbed specTraType profiles compared wiTh The normally Gaussian specTraType profiles characTerisTic of Naive CD8 T Cells from young mice. In addiTion, DNA sequence analysis formally demonsTraTed a loss of diversiTy associaTed wiTh skewed specTraType profiles. UnexpecTedly, we found mulTiple repeaTs of The same sequence in Naive T Cells from aged buT noT young mice, consisTenT wiTh clonal expansions previously described only in The memory T Cell pool. Clonal expansions among Naive T Cells suggesTs dysregulaTion in The normal homeosTaTic proliferaTive mechanisms ThaT operaTe in young mice To mainTain diversiTy in The Naive T Cell reperToire.
