PUBLICATIONS

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2022


Gassen RB, Borges TJ, Perez-Saez MJ, Zhang H, Al Jurdi A, Llinas-Mallol L, Aoyama B, Lima M, Pascual J, Sage PT, Murakami N, Riella LV. T cell depletion increases humoral responses by favoring T follicular helper cell expansion. Am. J. Transplant. 2022. Mar 23.

Zaiken MC, Flynn R, Paz KG, Rhee SY, Jin S, Mohamed FA, Saha A, Thangavelu G, Park PMC, Hemming ML, Sage PT, Sharpe AH, DuPage M, Bluestone JA, Panoskaltsis-Mortari A, Cutler CS, Koreth J, Antin JH, Soiffer RJ, Ritz J, Luznik L, Maillard I, Hill GR, MacDonald KP, Munn DH, Serody JS, Murphy WJ, Kean LS, Zhang Y, Bradner JE, Qi J, Blazar BR. BET-bromodomain and EZH2 inhibitor teated chronic GVHD mice have blunted germinal centers with distinct transcriptomes. Blood. 2022. Feb 28.

Cavazzoni CB, Hanson BL, Podesta MA, Bechu ED, Clement RL, Zhang H, Daccache J, Reyes-Robles T, Hett EC, Vora KA, Fadeyi OO, Oslund RC, Hazuda DJ, Sage PT. Follicular T cells Optimize the Germinal Center Response to SARS-CoV-2 Protein Vaccination in Mice. Cell Reports. 2022. Feb 1; 110399.

In this manuscript we studied how follicular T cells alter antibody responses during SARS-CoV-2 vaccination. Using genetic deletion studies and natural settings of aging we show that follicular T cells delicately balance affinity maturation and clonal expansion to optimize vaccine responses.

Jiang L, Yilmaz M, Uehara M, Cavazzoni CB, Kasinath V, Zhao J, Naini SM, Li X, Banouni N, Fiorina P, Shin SR, Tullius SG, Bromberg JS, Sage PT, Abdi R. Characterization of Leptin Receptor+ Stromal Cells in Lymph Node. Front. Immunol. 2022 Jan 17.

Clement RL, Hanson BL, Sage PT. Tfh-Mediated and Tfr-Suppressed Antigen-Driven IgG and IgE Assays. Methods Mol Biol. 2022; 2380:175-185.

Nanishi E, Borriello F, O’Meara TR, McGrath ME, Saito Y, Haupt RE, Seo HS, van Haren SD, Cavazzoni CB, Brook B, Barman S, Chen J, Diray-Arce J, Doss-Gollin S, De Leon M, Prevost-Reilly A, Chew K, Menon M, Song K, Xu AZ, Caradonna TM, Feldman J, Hauser BM, Schmidt AG, Sherman AC, Baden LR, Ernst RK, Dillen C, Weston SM, Johnson RM, Hammond HL, Mayer R, Burke A, Bottazzi ME, Hotez PJ, Strych U, Chang A, Yu J, Sage PT, Barouch DH, Dhe-Paganon S, Zanoni I, Ozonoff A, Frieman MB, Levy O, Dowling DJ. An Aluminum Hydroxide:CpG Adjuvant Enhances Protection Elicited by a SARS-CoV-2 Receptor Binding Domain Vaccine in Aged Mice. Sci. Transl. Med. 2022. Nov 16.


2021


Borges TJ, Murakami N, Lape IT, Gassen RB, Liu K, Cai S, Daccache J, Safa K, Shimizu T, Ohori S, Paterson AM, Cravedi P, Azzi J, Sage PT, Sharpe AH, Li XC, Riella LV. Overexpression of PD-1 on T Cells Promotes Tolerance in Cardiac Transplantation Via ICOS-dependent Mechanisms. JCI Insight. 2021 Dec 22;6(24);e142909.

Mohamed FA, Thangavelu G, Rhee SY, Sage PT, O’Connor RS, Rathmell JC, Blazar BR. Recent Metabolic Advances for Preventing and Treating Acute and Chronic Graft Versus Host Disease. Front. Immunol. 2021. Oct 12;12:757836.

Chong AS, Sage PT, Alegre ML. Regulation of Alloantibody Responses. Front. Cell Dev. Biol. 2021. Jul 8;9:706171. doi:10.3389/fcell.2021.706171.

Guglielmo C, Bin S, Cantarelli C, Hartzell S, Angeletti A, Donadei C, Cumpelik A, Anderson L, Cody E, Sage P, La Manna G, Fiaccadori E, Heeger P, Cravedi P. Erythropoietin Reduces Auto- and Allo-antibodies by Inhibiting T Follicular Helper Cell Differentiation. J. Am. Soc. Nephrol. 2021 Jul 14:ASN2021010098. doi:10.1681/ASN2021010098.

Mohammed MT, Cai S, Hanson BL, Zhang H, Clement RL, Daccache J, Cavazzoni CB, Blazar BR, Alessandrini A, Rennke HG, Chandraker A, Sage PT.  Follicular T Cells Mediate Donor Specific Antibody and Rejection after Solid Organ Transplantation. Am. J. Transplant. 2021. Jan 9. doi: 10.1111/ajt.16484

Donor specific antibodies (DSA) lead to antibody mediated rejection (AbMR) after kidney transplantation. Using pre-clinical models of kidney transplantation as well as Tfh-deleter and Tfr-deleter mice, we showed that Tfh and Tfr cells have essential roles in controlling DSA and AbMR in allogeneic kidney transplantation.

Tan CL, Kuchroo JR, Sage PT, Liang D, Francisco LM, Buck J, Thaker YR, Zhang Q, McArdel SL, Juneja VR, Lee SJ, Lovitch SB, Lian C, Murphy GF, Blazar BR, Vignali DAA, Freeman GJ, Sharpe AH. PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance. J. Exp. Med. 2021. 218(1):e20182232.


2020


Sage PT and Sharpe AH. The Multifaceted Functions of Follicular Regulatory T Cells. Curr. Opin. Immunol. 2020 Oct; 23:67:68-74. doi: 10.1016/j.coi.2020.10.009 

In this review we outline the current understanding of T follicular regulatory cell biology. We discuss how Tfr cells function to control foreign antigen-specific and auto-reactive B cell responses. We assess how alterations in this functionality can result in autoimmune disease.

Cavazzoni CB and Sage PT. Transplantation Tolerance: Expanded and Selective Roles for B Cells. Transplantation. 2020 Dec;104(12):2459-2460. doi: 10.1097/TP.0000000000003411

Ringel AE, Drivers JM, Baker GJ, Catozzi A, Garcia-Canaveras JC, Gassaway BM, Miller BC, Juneja VR, Nguyen TH, Joshi S, Yao CH, Yoon H, Sage PT, LaFleur MW, Trombley JD, Jacobson CA, Maliga Z, Gygi SP, Sorger PK, Rabinowitz JD, Sharpe AH, Haigis MC. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity. Cell. 2020. Dec 7:S0092.

Wara AK, Wang S, Wu C, Fang F, Hemming S, Weber BN, Aydogan CO, Tesmenitsky Y, Aliakbarian H, Hawse JR, Subramaniam M, Zhao L, Sage PT, Tavakkoli A, Garza A, Lynch L, Banks AS, Feinberg MW. KLF10 deficiency in CD4 T cells triggers obesity, insulin resistance, and fatty liver. Cell Rep. 2020. Dec 29; 33(13).

Sungnak W, Wagner A, Kowalczyk MS, Bod L, Kye YC, Sage PT, Sharpe AH, Sobel RA, Quintana FJ, Rozenblatt-Rosen O, Regev A, Wang C, Yosef N, Kuchroo VK. T follicular regulatory cell-derived fibrinogen-like protein 2 regulates production of autoantibodies and induction of systemic autoimmunity. Journal of Immunology. 2020. ji2000748

Turner JA, Stephen-Victor E, Wang S, Rivas MN, Abdel-Gadir A, Harb H, Cui Y, Fanny M, Charbonnier LM, Fong JJH, Benamar M, Wang L, Burton OT, Bansal K, Bry L, Zhu C, Li QZ, Clement RL, Oettgen HC, Crestani E, Rachid R, Sage PT, Chatila TA. Regulatory T cell-derived TGF-b1 controls multiple checkpoints governing allergy and autoimmunity. Immunity. 2020. S1074-7613(20)30414-3.

Cai S, Choi JY, Borges TJ, Zhang H, Miao J, Ichimura T, Li X, Xu S, Chu P, Eskandari SK, Allos H, Alhaddad JB, Muhsin SA, Yatim K, Riella LV, Sage PT, Chandraker AK, Azzi JR. Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo. Sci. Rep. 2020. 10(1):14249.

Shi Q, Carman CV, Chen Y, Sage PT, Xue F, Liang XM, Gilbert GE. Unexpected enhancement of FVIII immunogenicity by endothelial expression in lentivirus-transduced and transgenic mice. Blood. Adv. 2020. 4(10):2272-2285.

Jannsen E, Tohme M, Butts J, Giguere S, Sage PT, Velazquez FE, Kam C, Milin E, Das M, Sobh A, Al-Tamemi S, Luscinskas FW, Batista F, Geha RS. DOCK8 is essential for LFA-1-dependent positioning of T follicular helper cells in germinal centers. JCI Insight. 2020. 5(15):134508.


2019


Clement RL, Daccache J, Mohammed MT, Diallo A, Blazar BR, Kuchroo VK, Lovitch SB, Sharpe AH, Sage PT. Follicular regulatory T cells control humoral and allergic immunity by restraining early B cell responses. Nature Immunology. 2019. 20(10). PubMed PMID: 31477921. doi: 10.1038/s41590-019-0472-4.

In this study we developed a Tfr-deleter mouse to assess how Tfr cells regulate antibody responses. We show that Tfr cells regulate antigen specific antibody and memory B cell responses by regulating early germinal centers. We also describe a population of Tfh13 cells which have specialized roles in mediating IgE responses to allergens. Tfr cells potently regulate Tfh13 cells and IgE responses and loss of Tfr cells results in increased lung inflammation. These studies posit Tfh13 and Tfr cells as key regulators of allergic immunity.

Hou S, Clement R, Diallo AC, Blazar BR, Rudensky AY, Sharpe AH*, Sage PT*. FoxP3 and Ezh2 regulate Tfr suppressive function and transcriptional program. J Exp Med. 2019. 3(216). PubMed PMID: 30705058. doi: 10.1084/jem.20181134. 

In this study we identified a population of Tfr cells that naturally down regulate the transcription factor FoxP3 to become ex-Tfr cells with defective suppressive capacity. Furthermore, we determined that FoxP3 coopts the Tfh transcriptional program to induce a Tfr transcriptional program facilitating suppressive capacity. Lastly, we show that EZH2 is also essential in controlling the Tfr transcriptional program, but acts in distinct ways than FoxP3. These studies elucidate the Tfr transcriptional program which may facilitate the development of novel therapeutics to alter vaccine responses and autoimmunity.

Mohammed MT, Sage PT. Follicular T-cell regulation of alloantibody formation. Curr. Opin. Organ. Transplant. 2019. PubMed PMID: 31789953. doi: 10.1097/MOT.000000000000715. 

Paz K, Flynn R, Du J, Qi J, Luznik L, Maillard I, MacDonald KP, Hill GR, Serody JS, Murphy WJ, Sage PT, Sharpe AH, Miklos D, Cuter CS, Koreth J, Antin JH, Soiffer RJ, Ritz J, Bardner JE, Melnick AM, Blazar B. Small-molecule BCL6 inhibitor effectively treats mice with non-sclerodermatous chronic graft-versus-host disease.  Blood. 2019, 19(6). PubMed PMID: 30279226. doi: 10.1182/blood-2018-03-839993.

Wedel J, Bruneau S, Liu K, Kong SW, Sage PT, Sabatini DM, Laplante M, Briscoe DM. DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation. Am. J. Transplant. 2019, 19(1). PubMed PMID:29969188. doi: 10.1111/ajt.14995. 


2018


Sage PT. Preventing Antibody-mediated Rejection During Transplantation: The Potential of Tfr Cells. Transplantation. 2018 Oct; 102(10): 1597-1598. PubMed PMID: 29757906. doi: 10.1097/TP.0000000000002225. 

In this manuscript we review the current knowledge of the roles of Tfh and Tfr cells in controlling antibody mediated rejection during solid organ transplantation. Although correlation studies in patients and pre-clinical models point to important roles of Tfh and Tfr cells in controlling antibody mediated rejection, in depth mechanistic studies still need to be performed.

Ordikhani F, Uehara M, Kasinath V, Dai L, Eskandari SK, Bahmani B, Yonar M, Azzi JR, Haik Y, Sage PT, Murphy GF, Annabi N, Schatton T, Guleria I, Abdi R.  Targeting antigen-presenting cells by anti-PD-1 nanoparticles augments antitumor immunity.  JCI Insight. 2018 Oct 18;3(20). pii:122700. PubMed PMID:30333312. doi: 10.1172/jci.insight.122700.  

Maarouf OH, Uehara M, Kasinath V, Solhjou Z, Banouni N, Bahmani B, Jiang L, Yilman OA, Guleria I, Lovitch SB, Grogan JL, Fiorina P, Sage PT, Bromberg JS, McGrath MM, Abdi R. Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing. JCI Insight. 2018, 3(13): e120546. PubMed PMID: 29997302. doi: 10.1172/jci.insight.120546.

Sage PT*, Schildberg FA*, Sobel RA, Kuchroo VK, Freeman GJ, Sharpe AH. Dendritic cell PD-L1 limits autoimmunity and follicular T cell differentiation and function.  J Immunol. 2018;200(8)2592-602. PubMed PMID: 29531164. doi: 10.4049/jimmunol.1701231. 

In this study we developed a PD-L1 conditional knockout mouse to study the role of coinhibitory receptor ligation in Tfh and Tfr cell differentiation and function. We found that PD-L1 on dendritic cells inhibits Tfh and Tfr differentiation, whereas PD-L1 on B cells can control Tfh and Tfr cell functionality. These results point to multifaceted roles for coinhibitory receptors in controlling B cell responses.

2017


Zhang R*, Sage PT*, Finn K, Huynh A, Blazar BR, Marangoni F, Mempel TR, Sharpe AH, Turka LA. B cells drive autoimmunity in mice with CD28-deficient regulatory T cells. J Immunol. 2017;199(12):3972-80. PubMed PMID: 29093061.  doi: 10.4049/jimmunol.1700409.


2016


Sage PT, Ron-Harel N, Juneja VR, Sen DR, Maleri S, Sungnak W, Kuchroo VK, Haining WN, Chevrier N, Haigis M, Sharpe AH. Suppression by TFR cells leads to durable and selective inhibition of B cell effector function. Nature Immunology. 2016;17(12):1436-46. PubMed PMID: 27695002. doi: 10.1038/ni.3578.

In this study we assessed how Tfr cells regulate Tfh and B cell functionality using RNAseq and ATACseq. We found that Tfr cells cause a unique suppressed state in Tfh and B cells preventing effector gene expression and metabolic reprogramming while maintaining global transcriptional signatures. Epigenetic changes in B cells during suppression result in long-term durable defects in antibody responses. IL-21 can overcome Tfr suppression through metabolic reprogramming of B cells.

Sage PT, Sharpe AH. T follicular regulatory cells. Immunol Rev. 2016;271(1):246-59. PubMed PMID: 27088919. doi: 10.1111/imr.12411.

In this manuscript we review the current research on the role of Tfr cells in the context of disease. We also assess how coinhibitory receptors control Tfh and Tfr functionality.

Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A, Lovitch SB, Dephoure N, Satterstrom FK, Sheffer M, Spinelli JB, Gygi S, Rabinowitz JD, Sharpe AH, Haigis MC. Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation. Cell Metab. 2016;24(1):104-17. PubMed PMID: 27411012. doi: 10.1016/j.cmet.2016.06.007.


2015


Sage PT, Tan CL, Freeman GJ, Haigis M, Sharpe AH. Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging. Cell Rep. 2015;12(2):163-71. PubMed PMID: 26146074; PMCID: 4504745. doi: 10.1016/j.celrep.2015.06.015.

In this study we assessed how Tfh and Tfr cells alter with age and how these changes alter vaccine responses. We found that Tfh cells expanded in aged mice but had defects in promoting antibody responses. Tfr cells were also largely expanded and had potent suppressive capacity. The combination of defective Tfh cells and large percentages of functional Tfr cells results in diminished responses to vaccines with advanced age.

Sage PT, Sharpe AH. In Vitro Assay to Sensitively Measure T(FR) Suppressive Capacity and T(FH) Stimulation of B Cell Responses. Methods Mol Biol. 2015;1291:151-60. PubMed PMID: 25836309. doi: 10.1007/978-1-4939-2498-1_13.

In this protocol review we developed an in vitro Tfh-mediated B cell antibody class switch recombination and antibody secretion assay. With the addition of Tfr cells this assay can be used to assess Tfr suppression of B cell responses.

Paterson AM, Lovitch SB, Sage PT, Juneja VR, Lee Y, Trombley JD, Arancibia-Carcamo CV, Sobel RA, Rudensky AY, Kuchroo VK, Freeman GJ, Sharpe AH. Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity. J Exp Med. 2015;212(10):1603-21. PubMed PMID: 26371185; PMCID: 4577848. doi: 10.1084/jem.20141030.

Wang N, Halibozek PJ, Yigit B, Zhao H, O’Keeffe MS, Sage P, Sharpe A, Terhorst C. Negative Regulation of Humoral Immunity Due to Interplay between the SLAMF1, SLAMF5, and SLAMF6 Receptors. Front Immunol. 2015;6:158. PubMed PMID: 25926831; PMCID: PMC4396446. doi: 10.3389/fimmu.2015.00158.

Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, Townamchai N, Gerriets VA, Rathmell JC, Sharpe AH, Bluestone JA, Turka LA. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nature Immunology. 2015;16(2):188-96. PubMed PMID: 25559257; PMCID: 4297515. doi: 10.1038/ni.3077.


2014


Sage PT, Paterson AM, Lovitch SB, Sharpe AH. The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity. 2014;41(6):1026-39. PubMed PMID: 25526313. doi: 10.1016/j.immuni.2014.12.005.

In this study we assessed the role of CTLA-4 in controlling antibody responses. Through the use of conditional knockout strategies we determined that CTLA-4 inhibits Tfr differentiation but is essential for suppressive function. In addition, CTLA-4 inhibits Tfh cell differentiation as well as function. These studies posit CTLA-4 as having multifaceted roles in controlling antibody responses.

Sage PT, Alvarez D, Godec J, von Andrian UH, Sharpe AH. Circulating T follicular regulatory and helper cells have memory-like properties. J. Clin. Invest. 2014;124(12):5191-204. PubMed PMID: 25347469. doi: 10.1172/JCI76861.

In this study we elucidated the roles of circulating Tfh and Tfr cells. We found that circulating Tfh and Tfr cells in peripheral blood after vaccination had memory-like properties and quickly responded to antigen re-exposure to control antibody responses.

Cooper ZA*, Juneja VR*, Sage PT*, Frederick DT, Piris A, Mitra D, Lo JA, Hodi FS, Freeman GJ, Bosenberg MW, McMahon M, Flaherty KT, Fisher DE, Sharpe AH, Wargo JA. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. Cancer Immunol Res. 2014;2(7):643-54. PubMed PMID: 24903021; PMCID: 4097121. doi: 10.1158/2326-6066.CIR-13-0215.


2013


Sage PT, Francisco LM, Carman CV, Sharpe AH. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nature Immunology. 2013;14(2):152-61. PubMed PMID: 23242415. doi: 10.1038/ni.2496.

Martinelli R, Kamei M, Sage PT, Massol R, Varghese L, Sciuto T, Toporsian M, Dvorak AM, Kirchhausen T, Springer TA, Carman CV. Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds. J Cell Biol. 2013;201(3):449-65. PubMed PMID: 23629967; PMCID: PMC3639391. doi: 10.1083/jcb.201209077.


2012 and before


Sage PT, Varghese LM, Martinelli R, Sciuto TE, Kamei M, Dvorak AM, Springer TA, Sharpe AH, Carman CV. Antigen Recognition Is Facilitated by Invadosome-like Protrusions Formed by Memory/Effector T Cells. J Immunol. 2012;188(8):3686-99. PubMed PMID: 22442443. doi: 10.4049/jimmunol.1102594.

Jin Y, Chauhan SK, El Annan J, Sage PT, Sharpe AH, Dana R. A novel function for programmed death ligand-1 regulation of angiogenesis. Am J Pathol. 2011;178(4):1922-9. PubMed PMID: 21435468. doi: 10.1016/j.ajpath.2010.12.027. 

Riella LV, Watanabe T, Sage PT, Yang J, Yeung M, Azzi J, Vanguri V, Chandraker A, Sharpe AH, Sayegh MH, Najafian N. Essential role of PDL1 expression on nonhematopoietic donor cells in acquired tolerance to vascularized cardiac allografts. Am J Transplant. 2011;11(4):832-40. PubMed PMID: 21401869. doi: 10.1111/j.1600-6143.2011.03451.x.

Koduru S, Kumar L, Massaad MJ, Ramesh N, Le Bras S, Ozcan E, Oyoshi MK, Kaku M, Fujiwara Y, Kremer L, King S, Fuhlbrigge R, Rodig S, Sage P, Carman C, Alcaide P, Luscinskas FW, Geha RS. Cdc42 interacting protein 4 (CIP4) is essential for integrin-dependent T-cell trafficking. Proc Natl Acad Sci U S A. 2010;107(37):16252-6. PubMed PMID: 20805498.

Bonasio R, Carman CV, Kim E, Sage PT, Love KR, Mempel TR, Springer TA, von Andrian UH. Specific and covalent labeling of a membrane protein with organic fluorochromes and quantum dots. Proc Natl Acad Sci U S A. 2007;104(37):14753-8. PubMed PMID: 17785425.

Carman CV, Sage PT, Sciuto TE, de la Fuente MA, Geha RS, Ochs HD, Dvorak HF, Dvorak AM, Springer TA. Transcellular diapedesis is initiated by invasive podosomes. Immunity. 2007;26(6):784-97. PubMed PMID: 17570692.