Spatiotemporal Resolution of Germinal Center Tfh Cell Differentiation and Divergence from Central Memory CD4 T Cell Fate

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Jun 17

PMID 37330549

Authors

Fangming Zhu

Ryan J McMonigle

Andrew R Schroeder

Xianyou Xia

David Figge

Braxton D Greer

Edahi Gonzalez-Avalos

Diego O Sialer

Yin-Hu Wang

Kelly M Chandler

Adam J Getzler

Emily R Brown

Changchun Xiao

Olaf Kutsch

Yohsuke Harada

Matthew E Pipkin

Hui Hu

Affiliations

Soon will be listed here.

Abstract

Follicular helper T (Tfh) cells are essential for germinal center (GC) B cell responses. However, it is not clear which PD-1CXCR5Bcl6CD4 T cells will differentiate into PD-1CXCR5Bcl6 GC-Tfh cells and how GC-Tfh cell differentiation is regulated. Here, we report that the sustained Tigit expression in PD-1CXCR5CD4 T cells marks the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas TigitPD-1CXCR5CD4 T cells upregulate IL-7Rα to become CXCR5CD4 T memory cells with or without CCR7. We demonstrate that pre-Tfh cells undergo substantial further differentiation at the transcriptome and chromatin accessibility levels to become GC-Tfh cells. The transcription factor c-Maf appears critical in governing the pre-Tfh to GC-Tfh transition, and we identify Plekho1 as a stage-specific downstream factor regulating the GC-Tfh competitive fitness. In summary, our work identifies an important marker and regulatory mechanism of PD-1CXCR5CD4 T cells during their developmental choice between memory T cell fate and GC-Tfh cell differentiation.

Citing Articles

Early expansion of TIGIT+PD1+ effector memory CD4 T cells via agonistic effect of alefacept in new-onset type 1 diabetes.

Higdon L, Cooney L, Serti E, Suwannasaen D, Muir V, Wiedeman A J Immunol. 2025; 214(1):12-22.

PMID: 40073269 PMC: 11844141. DOI: 10.1093/jimmun/vkae014.

STING Deficiency Promotes Th17-Like Tfh to Aggravate the Experimental Autoimmune Uveitis.

Li Z, Liu X, Li Z, Xiao Z, Chen G, Li Y Invest Ophthalmol Vis Sci. 2025; 66(3):8.

PMID: 40042874 PMC: 11892529. DOI: 10.1167/iovs.66.3.8.

Enhanced Staphylococcus aureus protection by uncoupling of the α-toxin-ADAM10 interaction during murine neonatal vaccination.

Tomaszewski K, Blanchard M, Olaniyi R, Brenton H, Hayes S, Fatma F Nat Commun. 2024; 15(1):8702.

PMID: 39379345 PMC: 11461939. DOI: 10.1038/s41467-024-52714-7.

Synergistic blockade of TIGIT and PD-L1 increases type-1 inflammation and improves parasite control during murine blood-stage non-lethal infection.

Dookie R, Villegas-Mendez A, Cheeseman A, Jones A, Barroso R, Barrett J Infect Immun. 2024; 92(11):e0034524.

PMID: 39324794 PMC: 11556036. DOI: 10.1128/iai.00345-24.

[Progress of IL-21 and Tfh Mediated Immunotherapy in Non-small Cell Lung Cancer].

Liu X, Zhang Y, Zhang X, He G, Cai W Zhongguo Fei Ai Za Zhi. 2024; 27(7):550-558.

PMID: 39147710 PMC: 11331254. DOI: 10.3779/j.issn.1009-3419.2024.101.19.

References

Vinuesa C, Tangye S, Moser B, Mackay C . Follicular B helper T cells in antibody responses and autoimmunity. Nat Rev Immunol. 2005; 5(11):853-65. DOI: 10.1038/nri1714. View

Hatzi K, Nance J, Kroenke M, Bothwell M, Haddad E, Melnick A . BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. J Exp Med. 2015; 212(4):539-53. PMC: 4387288. DOI: 10.1084/jem.20141380. View

Johnston R, Poholek A, DiToro D, Yusuf I, Eto D, Barnett B . Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009; 325(5943):1006-10. PMC: 2766560. DOI: 10.1126/science.1175870. View

Martinez G, Hu J, Pereira R, Crampton J, Togher S, Bild N . Cutting Edge: NFAT Transcription Factors Promote the Generation of Follicular Helper T Cells in Response to Acute Viral Infection. J Immunol. 2016; 196(5):2015-9. PMC: 4761453. DOI: 10.4049/jimmunol.1501841. View

Yu D, Rao S, Tsai L, Lee S, He Y, Sutcliffe E . The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity. 2009; 31(3):457-68. DOI: 10.1016/j.immuni.2009.07.002. View

Cannons J, Qi H, Lu K, Dutta M, Gomez-Rodriguez J, Cheng J . Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84. Immunity. 2010; 32(2):253-65. PMC: 2830297. DOI: 10.1016/j.immuni.2010.01.010. View

Qi H, Cannons J, Klauschen F, Schwartzberg P, Germain R . SAP-controlled T-B cell interactions underlie germinal centre formation. Nature. 2008; 455(7214):764-9. PMC: 2652134. DOI: 10.1038/nature07345. View

Huang Z, Kang S, Li Y, Zak J, Shaabani N, Deng K . IFNAR1 signaling in NK cells promotes persistent virus infection. Sci Adv. 2021; 7(13). PMC: 7997497. DOI: 10.1126/sciadv.abb8087. View

Thomas P, Brown S, Morris M, Yue W, So J, Reynolds C . Physiological numbers of CD4+ T cells generate weak recall responses following influenza virus challenge. J Immunol. 2010; 184(4):1721-7. PMC: 2826830. DOI: 10.4049/jimmunol.0901427. View

10.

Yusuf I, Kageyama R, Monticelli L, Johnston R, DiToro D, Hansen K . Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J Immunol. 2010; 185(1):190-202. PMC: 2913439. DOI: 10.4049/jimmunol.0903505. View

11.

Sakai M, Serria M, Ikeda H, Yoshida K, Imaki J, Nishi S . Regulation of c-maf gene expression by Pax6 in cultured cells. Nucleic Acids Res. 2001; 29(5):1228-37. PMC: 29716. DOI: 10.1093/nar/29.5.1228. View

12.

Ciucci T, Vacchio M, Gao Y, Tomassoni Ardori F, Candia J, Mehta M . The Emergence and Functional Fitness of Memory CD4 T Cells Require the Transcription Factor Thpok. Immunity. 2019; 50(1):91-105.e4. PMC: 6503975. DOI: 10.1016/j.immuni.2018.12.019. View

13.

Nurieva R, Chung Y, Hwang D, Yang X, Kang H, Ma L . Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008; 29(1):138-49. PMC: 2556461. DOI: 10.1016/j.immuni.2008.05.009. View

14.

Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F . A validated regulatory network for Th17 cell specification. Cell. 2012; 151(2):289-303. PMC: 3503487. DOI: 10.1016/j.cell.2012.09.016. View

15.

Liu X, Chen X, Zhong B, Wang A, Wang X, Chu F . Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature. 2014; 507(7493):513-8. PMC: 4012617. DOI: 10.1038/nature12910. View

16.

Yeh C, Finney J, Okada T, Kurosaki T, Kelsoe G . Primary germinal center-resident T follicular helper cells are a physiologically distinct subset of CXCR5PD-1 T follicular helper cells. Immunity. 2022; 55(2):272-289.e7. PMC: 8842852. DOI: 10.1016/j.immuni.2021.12.015. View

17.

Stone E, Pepper M, Katayama C, Kerdiles Y, Lai C, Emslie E . ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity. 2015; 42(2):239-251. PMC: 4334393. DOI: 10.1016/j.immuni.2015.01.017. View

18.

Schroeder A, Zhu F, Hu H . Stepwise Tfh cell differentiation revisited: new advances and long-standing questions. Fac Rev. 2021; 10. PMC: 7894273. DOI: 10.12703/r/10-3. View

19.

Abe T, Sakaue-Sawano A, Kiyonari H, Shioi G, Inoue K, Horiuchi T . Visualization of cell cycle in mouse embryos with Fucci2 reporter directed by Rosa26 promoter. Development. 2012; 140(1):237-46. DOI: 10.1242/dev.084111. View

20.

Wu T, Shin H, Moseman E, Ji Y, Huang B, Harly C . TCF1 Is Required for the T Follicular Helper Cell Response to Viral Infection. Cell Rep. 2015; 12(12):2099-110. PMC: 4591235. DOI: 10.1016/j.celrep.2015.08.049. View