Single-cell Transcriptomics Identifies an Effectorness Gradient Shaping the Response of CD4 T Cells to Cytokines

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Apr 15

PMID 32286271

Citations 115

Authors

Eddie Cano-Gamez

Blagoje Soskic

Theodoros I Roumeliotis

Ernest So

Deborah J Smyth

Marta Baldrighi

David Wille

Nikolina Nakic

Jorge Esparza-Gordillo

Christopher G C Larminie

Paola G Bronson

David F Tough

Wendy C Rowan

Jyoti S Choudhary

Gosia Trynka

Affiliations

Soon will be listed here.

Abstract

Naïve CD4 T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. Here we use quantitative proteomics, bulk RNA-seq, and single-cell RNA-seq of over 40,000 human naïve and memory CD4 T cells to show that responses to cytokines differ substantially between these cell types. Memory T cells are unable to differentiate into the Th2 phenotype, and acquire a Th17-like phenotype in response to iTreg polarization. Single-cell analyses show that T cells constitute a transcriptional continuum that progresses from naïve to central and effector memory T cells, forming an effectorness gradient accompanied by an increase in the expression of chemokines and cytokines. Finally, we show that T cell activation and cytokine responses are influenced by the effectorness gradient. Our results illustrate the heterogeneity of T cell responses, furthering our understanding of inflammation.

Citing Articles

Innateness transcriptome gradients characterize mouse T lymphocyte populations.

Ascui G, Cedillo-Castelan V, Mendis A, Phung E, Liu H, Verstichel G J Immunol. 2025; 214(2):223-237.

PMID: 40073243 PMC: 11878997. DOI: 10.1093/jimmun/vkae015.

Cytotoxic KLRG1+ IL-7R- effector CD8+ T cells distinguish kidney transplant recipients controlling cytomegalovirus reactivation.

Sun Y, Sen S, Parmar R, Arakawa-Hoyt J, Cappelletti M, Rossetti M Front Immunol. 2025; 16:1542531.

PMID: 40028342 PMC: 11868092. DOI: 10.3389/fimmu.2025.1542531.

Role of CD4 T cells in cancer immunity: a single-cell sequencing exploration of tumor microenvironment.

An Q, Duan L, Wang Y, Wang F, Liu X, Liu C J Transl Med. 2025; 23(1):179.

PMID: 39953548 PMC: 11829416. DOI: 10.1186/s12967-025-06167-1.

Transcript-specific enrichment enables profiling of rare cell states via single-cell RNA sequencing.

Abay T, Stickels R, Takizawa M, Nalbant B, Hsieh Y, Hwang S Nat Genet. 2025; 57(2):451-460.

PMID: 39779958 DOI: 10.1038/s41588-024-02036-7.

Analysis of multi-condition single-cell data with latent embedding multivariate regression.

Ahlmann-Eltze C, Huber W Nat Genet. 2025; 57(3):659-667.

PMID: 39753773 PMC: 11906359. DOI: 10.1038/s41588-024-01996-0.

References

Turner M, Nedjai B, Hurst T, Pennington D . Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta. 2014; 1843(11):2563-2582. DOI: 10.1016/j.bbamcr.2014.05.014. View

Sallusto F . Heterogeneity of Human CD4(+) T Cells Against Microbes. Annu Rev Immunol. 2016; 34:317-34. DOI: 10.1146/annurev-immunol-032414-112056. View

Mosmann T, Cherwinski H, Bond M, Giedlin M, Coffman R . Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986; 136(7):2348-57. View

Le Gros G, Ben-Sasson S, Seder R, Finkelman F, Paul W . Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Immunol. 2008; 181(5):2943-51. View

Harrington L, Hatton R, Mangan P, Turner H, Murphy T, Murphy K . Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005; 6(11):1123-32. DOI: 10.1038/ni1254. View

Park H, Li Z, Yang X, Chang S, Nurieva R, Wang Y . A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005; 6(11):1133-41. PMC: 1618871. DOI: 10.1038/ni1261. View

Aijo T, Edelman S, Lonnberg T, Larjo A, Kallionpaa H, Tuomela S . An integrative computational systems biology approach identifies differentially regulated dynamic transcriptome signatures which drive the initiation of human T helper cell differentiation. BMC Genomics. 2012; 13:572. PMC: 3526425. DOI: 10.1186/1471-2164-13-572. View

Ullah U, Andrabi S, Tripathi S, Dirasantha O, Kanduri K, Rautio S . Transcriptional Repressor HIC1 Contributes to Suppressive Function of Human Induced Regulatory T Cells. Cell Rep. 2018; 22(8):2094-2106. PMC: 5842026. DOI: 10.1016/j.celrep.2018.01.070. View

Purvis H, Stoop J, Mann J, Woods S, Kozijn A, Hambleton S . Low-strength T-cell activation promotes Th17 responses. Blood. 2010; 116(23):4829-37. PMC: 3223073. DOI: 10.1182/blood-2010-03-272153. View

10.

Szabo S, Kim S, Costa G, Zhang X, Fathman C, Glimcher L . A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000; 100(6):655-69. DOI: 10.1016/s0092-8674(00)80702-3. View

11.

Zheng W, Flavell R . The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997; 89(4):587-96. DOI: 10.1016/s0092-8674(00)80240-8. View

12.

Yang X, Pappu B, Nurieva R, Akimzhanov A, Kang H, Chung Y . T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008; 28(1):29-39. PMC: 2587175. DOI: 10.1016/j.immuni.2007.11.016. View

13.

Fantini M, Becker C, Monteleone G, Pallone F, Galle P, Neurath M . Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004; 172(9):5149-53. DOI: 10.4049/jimmunol.172.9.5149. View

14.

Vahedi G, Takahashi H, Nakayamada S, Sun H, Sartorelli V, Kanno Y . STATs shape the active enhancer landscape of T cell populations. Cell. 2012; 151(5):981-93. PMC: 3509201. DOI: 10.1016/j.cell.2012.09.044. View

15.

Kanhere A, Hertweck A, Bhatia U, Gokmen M, Perucha E, Jackson I . T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nat Commun. 2012; 3:1268. PMC: 3535338. DOI: 10.1038/ncomms2260. View

16.

Samstein R, Arvey A, Josefowicz S, Peng X, Reynolds A, Sandstrom R . Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell. 2012; 151(1):153-66. PMC: 3493256. DOI: 10.1016/j.cell.2012.06.053. View

17.

Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W . Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A. 2010; 107(33):14751-6. PMC: 2930428. DOI: 10.1073/pnas.1003852107. View

18.

Veldhoen M, Uyttenhove C, Van Snick J, Helmby H, Westendorf A, Buer J . Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008; 9(12):1341-6. DOI: 10.1038/ni.1659. View

19.

Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-Hora M, Kodama T . Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2013; 20(1):62-8. DOI: 10.1038/nm.3432. View

20.

Cohen C, Crome S, MacDonald K, Dai E, Mager D, Levings M . Human Th1 and Th17 cells exhibit epigenetic stability at signature cytokine and transcription factor loci. J Immunol. 2011; 187(11):5615-26. DOI: 10.4049/jimmunol.1101058. View