An overview of T follicular cells in transplantation: spotlight on their clinical significance

References

• Rana A, Gruessner A, Agopian VG, et al. Survival benefit of solid-organ transplant in the United States. JAMA Surg. 2015 Mar 1;150(3):252–259.
   PubMed Web of Science ®Google Scholar
• Coemans M, Susal C, Dohler B, et al. Analyses of the short- and long-term graft survival after kidney transplantation in Europe between 1986 and 2015. Kidney Int. 2018 Nov;94(5):964–973.
   PubMed Web of Science ®Google Scholar
• Sellares J, de Freitas DG, Mengel M, et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012 Feb;12(2):388–399.
   PubMed Web of Science ®Google Scholar
• Baan CC, Knoop CJ, van Gelder T, et al. Anti-CD25 therapy reveals the redundancy of the intragraft cytokine network after clinical heart transplantation. Transplantation. 1999 Mar 27;67(6):870–876.
   PubMed Web of Science ®Google Scholar
• Gaston RS, Cecka JM, Kasiske BL, et al. Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. Transplantation. 2010 Jul 15;90(1):68–74.
   PubMed Web of Science ®Google Scholar
• Baan CC. In case you missed it-basic science advances in transplantation 2017. Transplantation. 2018 Jun;102(6):932–934.
   PubMed Web of Science ®Google Scholar
• Loupy A, Haas M, Solez K, et al. The banff 2015 kidney meeting report: current challenges in rejection classification and prospects for adopting molecular pathology. Am J Transplant. 2017 Jan;17(1):28–41.
   PubMed Web of Science ®Google Scholar
• Frank R, Dean SA, Molina MR, et al. Correlations of lymphocyte subset infiltrates with donor-specific antibodies and acute antibody-mediated rejection in endomyocardial biopsies. Cardiovasc Pathol. 2015 May-Jun;24(3):168–172.
   PubMed Web of Science ®Google Scholar
• Zarkhin V, Kambham N, Li L, et al. Characterization of intra-graft B cells during renal allograft rejection. Kidney Int. 2008 Sep;74(5):664–673.
   PubMed Web of Science ®Google Scholar
• Heidt S, Vergunst M, Anholts JDH, et al. Presence of intragraft B cells during acute renal allograft rejection is accompanied by changes in peripheral blood B cell subsets. Clin Exp Immunol. 2019 Jun;196(3):403–414.
   PubMed Web of Science ®Google Scholar
• Loupy A, Lefaucheur C. Antibody-mediated rejection of solid-organ allografts. N Engl J Med. 2018 Sep 20; 379(12):1150–1160.
   PubMed Web of Science ®Google Scholar
• Carpio VN, Noronha Ide L, Martins HL, et al. Expression patterns of B cells in acute kidney transplant rejection. Exp Clin Transplant. 2014 Oct;12(5):405–414.
   PubMed Web of Science ®Google Scholar
• de Leur K, Clahsen-van Groningen MC, van den Bosch TPP, et al. Characterization of ectopic lymphoid structures in different types of acute renal allograft rejection. Clin Exp Immunol. 2018 May;192(2):224–232.
   PubMed Web of Science ®Google Scholar
• Thaunat O, Field AC, Dai J, et al. Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response. Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14723–14728.
   PubMed Web of Science ®Google Scholar
• de Graav GN, Dieterich M, Hesselink DA, et al. Follicular T helper cells and humoral reactivity in kidney transplant patients. Clin Exp Immunol. 2015 May;180(2):329–340.
   PubMed Web of Science ®Google Scholar
• Wang Y, Shi J, Yan J, et al. Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells. Nat Immunol. 2017 Aug;18(8):921–930.
   PubMed Web of Science ®Google Scholar
• Tangye SG, Ma CS, Brink R, et al. The good, the bad and the ugly - TFH cells in human health and disease. Nat Rev Immunol. 2013 Jun;13(6):412–426.
   PubMed Web of Science ®Google Scholar
• Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621–663.
   PubMed Web of Science ®Google Scholar
• Walters GD, Vinuesa CG. T follicular helper cells in transplantation. Transplantation. 2016 Aug;100(8):1650–1655.
   PubMed Web of Science ®Google Scholar
• Zhu Y, Zou L, Liu YC. T follicular helper cells, T follicular regulatory cells and autoimmunity. Int Immunol. 2016 Apr;28(4):173–179.
   PubMed Web of Science ®Google Scholar
• Hardtke S, Ohl L, Forster R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood. 2005 Sep 15;106(6):1924–1931.
   PubMed Web of Science ®Google Scholar
• Baan CC, de Graav GN, Boer K. T follicular helper cells in transplantation: the target to attenuate antibody-mediated allogeneic responses? Curr Transplant Rep. 2014;1(3):166–172.
   PubMedGoogle Scholar
• Berek C, Berger A, Apel M. Maturation of the immune response in germinal centers. Cell. 1991;67:1121–1129.
   PubMed Web of Science ®Google Scholar
• Jacob J, Kelsoe G, Rajewsky K, et al. Intraclonal generation of antibody mutants in germinal centres. Nature. 1991 Dec 5;354(6352):389–392.
   PubMed Web of Science ®Google Scholar
• Wiesner M, Zentz C, Mayr C, et al. Conditional immortalization of human B cells by CD40 ligation. PLoS One. 2008 Jan 23;3(1):e1464.
   PubMed Web of Science ®Google Scholar
• Linterman MA, Beaton L, Yu D, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med. 2010 Feb 15;207(2):353–363.
   PubMed Web of Science ®Google Scholar
• Yu D, Rao S, Tsai LM, et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity. 2009;31(3):457–468.
   PubMed Web of Science ®Google Scholar
• Nurieva RI, Chung Y, Martinez GJ, et al. Bcl6 mediates the development of T follicular helper cells. Science. 2009 Aug 21;325(5943):1001–1005.
   PubMed Web of Science ®Google Scholar
• Johnston RJ, Poholek AC, DiToro D, et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009 Aug 21;325(5943):1006–1010.
   PubMed Web of Science ®Google Scholar
• Shi J, Hou S, Fang Q, et al. PD-1 controls follicular T helper cell positioning and function. Immunity. 2018 Aug 21;49(2):264–274 e264.
   PubMed Web of Science ®Google Scholar
• Deenick EK, Chan A, Ma CS, et al. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity. 2010;33(2):241–253.
   PubMed Web of Science ®Google Scholar
• Choi YS, Eto D, Yang JA, et al. Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J Immunol. 2013 Apr 1;190(7):3049–3053.
   PubMed Web of Science ®Google Scholar
• Nakayamada S, Kanno Y, Takahashi H, et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity. 2011;35(6):919–931.
   PubMed Web of Science ®Google Scholar
• Vogelzang A, McGuire HM, Yu D, et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity. 2008 Jul 18;29(1):127–137.
   PubMed Web of Science ®Google Scholar
• Ise W, Kohyama M, Schraml BU, et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat Immunol. 2011 Jun;12(6):536–543.
   PubMed Web of Science ®Google Scholar
• Liu X, Chen X, Zhong B, et al. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature. 2014 Mar 27;507(7493):513–518.
   PubMed Web of Science ®Google Scholar
• Choi YS, Gullicksrud JA, Xing S, et al. LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat Immunol. 2015 Sep;16(9):980–990.
   PubMed Web of Science ®Google Scholar
• Meli AP, Fontes G, Avery DT, et al. The integrin LFA-1 controls T follicular helper cell generation and maintenance. Immunity. 2016 Oct 18;45(4):831–846.
   PubMed Web of Science ®Google Scholar
• Hao Y, Wang Y, Liu X, et al. The kinase complex mTOR complex 2 promotes the follicular migration and functional maturation of differentiated follicular helper CD4(+) T cells during viral infection. Front Immunol. 2018;9:1127.
   PubMed Web of Science ®Google Scholar
• He L, Gu W, Wang M, et al. Extracellular matrix protein 1 promotes follicular helper T cell differentiation and antibody production. Proc Natl Acad Sci U S A. 2018 Aug 21;115(34):8621–8626.
   PubMed Web of Science ®Google Scholar
• Geng J, Wei H, Shi B, et al. Bach2 negatively regulates T follicular helper cell differentiation and is critical for CD4(+) T cell memory. J Immunol. 2019 May 15;202(10):2991–2998.
   PubMed Web of Science ®Google Scholar
• Johnston RJ, Choi YS, Diamond JA, et al. STAT5 is a potent negative regulator of TFH cell differentiation. J Exp Med. 2012 Feb 13;209(2):243–250.
   PubMed Web of Science ®Google Scholar
• Xu H, Li X, Liu D, et al. Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility. Nature. 2013 Apr 25;496(7446):523–527.
   PubMed Web of Science ®Google Scholar
• Wan Z, Lin Y, Zhao Y, et al. TFH cells in bystander and cognate interactions with B cells. Immunol Rev. 2019 Mar;288(1):28–36.
   PubMed Web of Science ®Google Scholar
• Xin G, Zander R, Schauder DM, et al. Single-cell RNA sequencing unveils an IL-10-producing helper subset that sustains humoral immunity during persistent infection. Nat Commun. 2018 Nov 28;9(1):5037.
   PubMedGoogle Scholar
• Lu KT, Kanno Y, Cannons JL, et al. Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. Immunity. 2011 Oct 28;35(4):622–632.
   PubMed Web of Science ®Google Scholar
• Zotos D, Coquet JM, Zhang Y, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med. 2010 Feb 15;207(2):365–378.
   PubMed Web of Science ®Google Scholar
• de Leur K, Dor FJ, Dieterich M, et al. IL-21 receptor antagonist inhibits differentiation of B cells toward plasmablasts upon alloantigen stimulation. Front Immunol. 2017;8:306.
   PubMed Web of Science ®Google Scholar
• Yusuf I, Kageyama R, Monticelli L, et al. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J Immunol. 2010 Jul 1;185(1):190–202.
   PubMed Web of Science ®Google Scholar
• Papa I, Saliba D, Ponzoni M, et al. TFH-derived dopamine accelerates productive synapses in germinal centres. Nature. 2017 Jul 20;547(7663):318–323.
   PubMed Web of Science ®Google Scholar
• Morita R, Schmitt N, Bentebibel SE, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011 Jan 28;34(1):108–121.
   PubMed Web of Science ®Google Scholar
• Zhang K, Sun YL, Zhou SN, et al. Circulating CXCR3-CCR6-CXCR5(+)CD4(+) T cells are associated with acute allograft rejection in liver transplantation. Immunol Lett. 2019 Mar 5;S0165-2478(0118)30310–30319. DOI:10.31016/j.imlet.32019.30303.30003.
   Web of Science ®Google Scholar
• Cano-Romero FL, Laguna Goya R, Utrero-Rico A, et al. Longitudinal profile of circulating T follicular helper lymphocytes parallels anti-HLA sensitization in renal transplant recipients. Am J Transplant. 2019 Jan;19(1):89–97.
   PubMed Web of Science ®Google Scholar
• He J, Tsai LM, Leong YA, et al. Circulating precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity. 2013 Oct 17;39(4):770–781.
   PubMed Web of Science ®Google Scholar
• La Muraglia GM 2nd, Wagener ME, Ford ML, et al. Circulating T follicular helper cells are a biomarker of humoral alloreactivity and predict donor-specific antibody formation after transplantation. Am J Transplant. 2019 Jun 28. doi: 10.1111/ajt.15517. [Epub ahead of print]
   Web of Science ®Google Scholar
• Schmitt N, Bentebibel SE, Ueno H. Phenotype and functions of memory Tfh cells in human blood. Trends Immunol. 2014 Sep;35(9):436–442.
   PubMed Web of Science ®Google Scholar
• Haynes NM, Allen CD, Lesley R, et al. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J Immunol. 2007 Oct 15;179(8):5099–5108.
   PubMed Web of Science ®Google Scholar
• Chevalier N, Jarrossay D, Ho E, et al. CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses. J Immunol. 2011 May 15;186(10):5556–5568.
   PubMed Web of Science ®Google Scholar
• Locci M, Havenar-Daughton C, Landais E, et al. Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity. 2013 Oct 17;39(4):758–769.
   PubMed Web of Science ®Google Scholar
• Byford ET, Carr M, Ladikou E, et al. Circulating Tfh1 (cTfh1) cell numbers and PD1 expression are elevated in low-grade B-cell non-Hodgkin’s lymphoma and cTfh gene expression is perturbed in marginal zone lymphoma. PLoS One. 2018;13(1):e0190468.
   PubMed Web of Science ®Google Scholar
• Le Coz C, Joublin A, Pasquali JL, et al. Circulating TFH subset distribution is strongly affected in lupus patients with an active disease. PLoS One. 2013;8(9):e75319.
   PubMed Web of Science ®Google Scholar
• Arroyo-Villa I, Bautista-Caro MB, Balsa A, et al. Constitutively altered frequencies of circulating follicullar helper T cell counterparts and their subsets in rheumatoid arthritis. Arthritis Res Ther. 2014 Dec 5;16(6):500.
   PubMed Web of Science ®Google Scholar
• Zhao J, Chen Y, Zhao Q, et al. Increased circulating Tfh17 and PD-1(+)Tfh cells are associated with autoantibodies in Hashimoto’s thyroiditis. Autoimmunity. 2018 Nov;51(7):352–359.
   PubMed Web of Science ®Google Scholar
• Zhou H, Hu B, Huang N, et al. Aberrant T cell subsets and cytokines expression profile in systemic lupus erythematosus. Clin Rheumatol. 2018 Sep;37(9):2405–2413.
   PubMed Web of Science ®Google Scholar
• Ricard L, Jachiet V, Malard F, et al. Circulating follicular helper T cells are increased in systemic sclerosis and promote plasmablast differentiation through the IL-21 pathway which can be inhibited by ruxolitinib. Ann Rheum Dis. 2019 Apr;78(4):539–550.
   PubMed Web of Science ®Google Scholar
• Kenefeck R, Wang CJ, Kapadi T, et al. Follicular helper T cell signature in type 1 diabetes. J Clin Invest. 2015 Jan;125(1):292–303.
   PubMed Web of Science ®Google Scholar
• Kim EJ, Kwun J, Gibby AC, et al. Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection. Am J Transplant. 2014 Jan;14(1):59–69.
   PubMed Web of Science ®Google Scholar
• Macedo C, Hadi K, Walters J, et al. Impact of induction therapy on circulating T follicular helper cells and subsequent donor-specific antibody formation after kidney transplant. Kidney Int Rep. 2019 Mar;4(3):455–469.
   PubMed Web of Science ®Google Scholar
• Iwasaki K, Kitahata N, Hiramitsu T, et al. Increased CD40L+PD-1+ follicular helper T cells (Tfh) as a biomarker for predicting calcineurin inhibitor sensitivity against Tfh-mediated B-cell activation/antibody production after kidney transplantation. Int Immunol. 2018 Jul 24;30(8):345–355.
   PubMed Web of Science ®Google Scholar
• Chenouard A, Chesneau M, Bui Nguyen L, et al. Renal operational tolerance is associated with a defect of blood Tfh cells that exhibit impaired B cell help. Am J Transplant. 2017 Jun;17(6):1490–1501.
   PubMed Web of Science ®Google Scholar
• Conlon TM, Saeb-Parsy K, Cole JL, et al. Germinal center alloantibody responses are mediated exclusively by indirect-pathway CD4 T follicular helper cells. J Immunol. 2012 Mar 15;188(6):2643–2652.
   PubMed Web of Science ®Google Scholar
• Qureshi MS, Alsughayyir J, Chhabra M, et al. Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy. J Autoimmun. 2019;98:44–58.
   PubMed Web of Science ®Google Scholar
• Vinuesa CG, Sanz I, Cook MC. Dysregulation of germinal centres in autoimmune disease [Review Article]. Nat Rev Immunol. 2009 Dec;9(12):845–857.
   PubMed Web of Science ®Google Scholar
• Uwadiae FI, Pyle CJ, Walker SA, et al. Targeting the ICOS/ICOS-L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease. Allergy. 2019 Apr;74(4):650–662.
   PubMed Web of Science ®Google Scholar
• Basso K, Dalla-Favera R. Germinal centres and B cell lymphomagenesis. Nat Rev Immunol. 2015 Mar;15(3):172–184.
   PubMed Web of Science ®Google Scholar
• Linterman MA, Pierson W, Lee SK, et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med. 2011 Jul 24;17(8):975–982.
   PubMed Web of Science ®Google Scholar
• Fonseca VR, Ribeiro F, Graca L. T follicular regulatory (Tfr) cells: dissecting the complexity of Tfr-cell compartments. Immunol Rev. 2019 Mar;288(1):112–127.
   PubMed Web of Science ®Google Scholar
• Wing JB, Tekguc M, Sakaguchi S. Control of Germinal center responses by T-follicular regulatory cells. Front Immunol. 2018;9:1910.
   PubMed Web of Science ®Google Scholar
• Young JS, Chen J, Miller ML, et al. Delayed cytotoxic T lymphocyte-associated protein 4-immunoglobulin treatment reverses ongoing alloantibody responses and rescues allografts from acute rejection. Am J Transplant. 2016 Aug;16(8):2312–2323.
   PubMed Web of Science ®Google Scholar
• Chung Y, Tanaka S, Chu F, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011 Jul 24;17(8):983–988.
   PubMed Web of Science ®Google Scholar
• Zhang R, Sage PT, Finn K, et al. B cells drive autoimmunity in mice with CD28-deficient regulatory T cells. J Immunol. 2017 Dec 15;199(12):3972–3980.
   PubMed Web of Science ®Google Scholar
• Sage PT, Francisco LM, Carman CV, et al. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol. 2013 Feb;14(2):152–161.
   PubMed Web of Science ®Google Scholar
• Wing JB, Ise W, Kurosaki T, et al. Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. Immunity. 2014 Dec 18;41(6):1013–1025.
   PubMed Web of Science ®Google Scholar
• Botta D, Fuller MJ, Marquez-Lago TT, et al. Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol. 2017 Nov;18(11):1249–1260.
   PubMed Web of Science ®Google Scholar
• Ding Y, Li J, Yang P, et al. Interleukin-21 promotes germinal center reaction by skewing the follicular regulatory T cell to follicular helper T cell balance in autoimmune BXD2 mice. Arthritis Rheumatol. 2014 Sep;66(9):2601–2612.
   PubMed Web of Science ®Google Scholar
• Vaeth M, Muller G, Stauss D, et al. Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression. J Exp Med. 2014 Mar 10;211(3):545–561.
   PubMed Web of Science ®Google Scholar
• Qi H, Cannons JL, Klauschen F, et al. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature. 2008 Oct 9;455(7214):764–769.
   PubMed Web of Science ®Google Scholar
• Xu L, Huang Q, Wang H, et al. The kinase mTORC1 promotes the generation and suppressive function of follicular regulatory T cells. Immunity. 2017 Sep 19;47(3):538–551 e535.
   PubMed Web of Science ®Google Scholar
• Chinen T, Kannan AK, Levine AG, et al. An essential role for the IL-2 receptor in treg cell function. Nat Immunol. 2016 Nov;17(11):1322–1333.
   PubMed Web of Science ®Google Scholar
• Chorro L, Suzuki M, Chin SS, et al. Interleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape. Nat Commun. 2018 Dec 18;9(1):5368.
   PubMedGoogle Scholar
• Ballesteros-Tato A, Leon B, Graf BA, et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity. 2012 May 25;36(5):847–856.
   PubMed Web of Science ®Google Scholar
• Ritvo PG, Churlaud G, Quiniou V, et al. Tfr cells lack IL-2Ralpha but express decoy IL-1R2 and IL-1Ra and suppress the IL-1-dependent activation of Tfh cells. Sci Immunol. 2017 Sep 8;2(15):eaan0368. .
   PubMed Web of Science ®Google Scholar
• Wing JB, Kitagawa Y, Locci M, et al. A distinct subpopulation of CD25(-) T-follicular regulatory cells localizes in the germinal centers. Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):E6400–E6409.
   PubMed Web of Science ®Google Scholar
• Sage PT, Sharpe AH. T follicular regulatory cells. Immunol Rev. 2016 May;271(1):246–259.
   PubMed Web of Science ®Google Scholar
• Sage PT, Sharpe AH. T follicular regulatory cells in the regulation of B cell responses. Trends Immunol. 2015 Jul;36(7):410–418.
   PubMed Web of Science ®Google Scholar
• Miles B, Connick E. Control of the germinal center by follicular regulatory T cells during infection. Front Immunol. 2018;9:2704.
   PubMed Web of Science ®Google Scholar
• Wang CJ, Heuts F, Ovcinnikovs V, et al. CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):524–529.
   PubMed Web of Science ®Google Scholar
• Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008 Oct 10;322(5899):271–275.
   PubMed Web of Science ®Google Scholar
• Zhao DM, Thornton AM, DiPaolo RJ, et al. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood. 2006 May 15;107(10):3925–3932.
   PubMed Web of Science ®Google Scholar
• Sage PT, Paterson AM, Lovitch SB, et al. 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):1026–1039.
   PubMed Web of Science ®Google Scholar
• McCarron MJ, Marie JC. TGF-beta prevents T follicular helper cell accumulation and B cell autoreactivity. J Clin Invest. 2014 Oct;124(10):4375–4386.
   PubMed Web of Science ®Google Scholar
• Laidlaw BJ, Lu Y, Amezquita RA, et al. Interleukin-10 from CD4 (+) follicular regulatory T cells promotes the germinal center response. Sci Immunol. 2017 Oct 20;2:16.
   Web of Science ®Google Scholar
• Levy Y, Brouet JC. Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Invest. 1994;93(1):424–428.
   PubMed Web of Science ®Google Scholar
• Wu H, Chen Y, Liu H, et al. Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice. Eur J Immunol. 2016 May;46(5):1152–1161.
   PubMed Web of Science ®Google Scholar
• Chen W, Bai J, Huang H, et al. Low proportion of follicular regulatory T cell in renal transplant patients with chronic antibody-mediated rejection. Sci Rep. 2017 May 2;7(1):1322.
   PubMedGoogle Scholar
• McDonald-Hyman C, Flynn R, Panoskaltsis-Mortari A, et al. Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner. Blood. 2016;128(7):1013–1017.
   PubMed Web of Science ®Google Scholar
• Braza F, Dugast E, Panov I, et al. Central Role of CD45RA- Foxp3hi memory regulatory T cells in clinical kidney transplantation tolerance. J Am Soc Nephrol. 2015 Aug;26(8):1795–1805.
   PubMed Web of Science ®Google Scholar
• Li YM, Li Y, Shi YY, et al. Impact of immunosuppressive drugs on circulating Tfh cells in kidney transplant recipients: A pilot study. Transpl Immunol. 2018;46:1–7.
   PubMed Web of Science ®Google Scholar
• Wallin EF, Hill DL, Linterman MA, et al. The calcineurin inhibitor tacrolimus specifically suppresses human T follicular helper cells. Front Immunol. 2018;9:1184.
   PubMed Web of Science ®Google Scholar
• Hoskova L, Malek I, Kopkan L, et al. Pathophysiological mechanisms of calcineurin inhibitor-induced nephrotoxicity and arterial hypertension. Physiol Res. 2017 May 4;66(2):167–180.
   PubMed Web of Science ®Google Scholar
• Martinez GJ, Hu JK, Pereira RM, et al. Cutting edge: NFAT transcription factors promote the generation of follicular helper T cells in response to acute viral infection. J Immunol. 2016 Mar 1;196(5):2015–2019.
   PubMed Web of Science ®Google Scholar
• Wallin EF. T follicular regulatory cells and antibody responses in transplantation. Transplantation. 2018 Oct;102(10):1614–1623.
   PubMed Web of Science ®Google Scholar
• Menon MC, Murphy B. Maintenance immunosuppression in renal transplantation. Curr Opin Pharmacol. 2013 Aug;13(4):662–671.
   PubMed Web of Science ®Google Scholar
• van der Mast BJ, van Besouw NM, Witvliet MD, et al. Formation of donor-specific human leukocyte antigen antibodies after kidney transplantation: correlation with acute rejection and tapering of immunosuppression. Transplantation. 2003 Mar 27;75(6):871–877.
   PubMed Web of Science ®Google Scholar
• Filler G, Todorova EK, Bax K, et al. Minimum mycophenolic acid levels are associated with donor-specific antibody formation. Pediatr Transplant. 2016 Feb;20(1):34–38.
   PubMed Web of Science ®Google Scholar
• de Graav GN, Hesselink DA, Dieterich M, et al. Belatacept does not inhibit follicular T cell-dependent B-cell differentiation in kidney transplantation. Front Immunol. 2017;8:641.
   PubMed Web of Science ®Google Scholar
• Chen CC, Koenig A, Saison C, et al. CD4+ T cell help is mandatory for naive and memory donor-specific antibody responses: impact of therapeutic immunosuppression. Front Immunol. 2018;9:275.
   PubMed Web of Science ®Google Scholar
• Dahdal S, Saison C, Valette M, et al. Residual activatability of circulating Tfh17 predicts humoral response to thymodependent antigens in patients on therapeutic immunosuppression. Front Immunol. 2018;9:3178.
   PubMed Web of Science ®Google Scholar
• Bouvy AP, Kho MM, Klepper M, et al. Kinetics of homeostatic proliferation and thymopoiesis after rATG induction therapy in kidney transplant patients. Transplantation. 2013 Nov 27;96(10):904–913.
   PubMed Web of Science ®Google Scholar
• Leibler C, Thiolat A, Henique C, et al. Control of humoral response in renal transplantation by belatacept depends on a direct effect on B cells and impaired T follicular helper-B cell crosstalk. J Am Soc Nephrol. 2018 Mar;29(3):1049–1062.
   PubMed Web of Science ®Google Scholar
• Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant. 2005 Mar;5(3):443–453.
   PubMed Web of Science ®Google Scholar
• Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010 Mar;10(3):535–546.
   PubMed Web of Science ®Google Scholar
• Badell IR, La Muraglia GM 2nd, Liu D, et al. Selective CD28 blockade results in superior inhibition of donor-specific T follicular helper cell and antibody responses relative to CTLA4-Ig. Am J Transplant. 2018 Jan;18(1):89–101.
   PubMed Web of Science ®Google Scholar
• Ville S, Poirier N, Branchereau J, et al. Anti-CD28 antibody and belatacept exert differential effects on mechanisms of renal allograft rejection. J Am Soc Nephrol. 2016 Dec;27(12):3577–3588.
   PubMed Web of Science ®Google Scholar
• Cicalese MP, Gerosa J, Baronio M, et al. Circulating follicular helper and follicular regulatory T cells are severely compromised in human CD40 deficiency: a case report. Front Immunol. 2018;9:1761.
   PubMed Web of Science ®Google Scholar
• Eto D, Lao C, DiToro D, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One. 2011 Mar 14;6(3):e17739.
   PubMed Web of Science ®Google Scholar
• Jordan SC, Choi J, Kim I, et al. Interleukin-6, A cytokine critical to mediation of inflammation, autoimmunity and allograft rejection: therapeutic implications of il-6 receptor blockade. Transplantation. 2017 Jan;101(1):32–44.
   PubMed Web of Science ®Google Scholar
• Hippen KL, Bucher C, Schirm DK, et al. Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes. Blood. 2012 Jan 12;119(2):619–628.
   PubMed Web of Science ®Google Scholar
• de Leur K, Luk F, van den Bosch TPP, et al. The effects of an IL-21 receptor antagonist on the alloimmune response in a humanized mouse skin transplant model. Transplantation. 2019 Oct;103(10):2065–2074.
   PubMedGoogle Scholar
• van Besouw NM, Yan L, de Kuiper R, et al. The Number of Donor-Specific IL-21 Producing Cells Before and After Transplantation Predicts Kidney Graft Rejection. Front Immunol. 2019;10:748.
   PubMed Web of Science ®Google Scholar
• Nickerson PW, Rush DN. Begin at the beginning to prevent the end. J Am Soc Nephrol. 2015 Jul;26(7):1483–1485.
   PubMed Web of Science ®Google Scholar