The Initial Phase of an Immune Response Functions to Activate Regulatory T Cells

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2009 Jun 23

PMID 19542444

Citations 83

Authors

William E OGorman

Hans Dooms

Steve H Thorne

Wilson F Kuswanto

Erin F Simonds

Peter O Krutzik

Garry P Nolan

Abul K Abbas

Affiliations

Soon will be listed here.

Abstract

An early reaction of CD4(+) T lymphocytes to Ag is the production of cytokines, notably IL-2. To detect cytokine-dependent responses, naive Ag-specific T cells were stimulated in vivo and the presence of phosphorylated STAT5 molecules was used to identify the cell populations responding to IL-2. Within hours of T cell priming, IL-2-dependent STAT5 phosphorylation occurred primarily in Foxp3(+) regulatory T cells. In contrast, the Ag-specific T cells received STAT5 signals only after repeated Ag exposure or memory differentiation. Regulatory T cells receiving IL-2 signals proliferated and developed enhanced suppressive activity. These results indicate that one of the earliest events in a T cell response is the activation of endogenous regulatory cells, potentially to prevent autoimmunity.

Citing Articles

Increased Frequency of Circulating Activated FOXP3 Regulatory T Cell Subset in Patients with Chronic Lymphocytic Leukemia Is Associated with the Estimate of the Size of the Tumor Mass, STAT5 Signaling and Disease Course during Follow-Up of Patients....

Roskar Z, Dreisinger M, Homsak E, Avcin T, Bevc S, Goropevsek A Cancers (Basel). 2024; 16(18).

PMID: 39335199 PMC: 11430700. DOI: 10.3390/cancers16183228.

CD8-Targeted IL2 Unleashes Tumor-Specific Immunity in Human Cancer Tissue by Reviving the Dysfunctional T-cell Pool.

Kaptein P, Slingerland N, Metoikidou C, Prinz F, Brokamp S, Machuca-Ostos M Cancer Discov. 2024; 14(7):1226-1251.

PMID: 38563969 PMC: 11215409. DOI: 10.1158/2159-8290.CD-23-1263.

Regulatory T cells use heparanase to access IL-2 bound to extracellular matrix in inflamed tissue.

Martinez H, Koliesnik I, Kaber G, Reid J, Nagy N, Barlow G Nat Commun. 2024; 15(1):1564.

PMID: 38378682 PMC: 10879116. DOI: 10.1038/s41467-024-45012-9.

Mesoscience in cell biology and cancer research.

Qian H, Beltran A Cancer Innov. 2023; 1(4):271-284.

PMID: 38089088 PMC: 10686186. DOI: 10.1002/cai2.33.

The role of CD4 T cells in tumor and chronic viral immune responses.

Xie L, Fang J, Yu J, Zhang W, He Z, Ye L MedComm (2020). 2023; 4(5):e390.

PMID: 37829505 PMC: 10565399. DOI: 10.1002/mco2.390.

References

Krutzik P, Nolan G . Intracellular phospho-protein staining techniques for flow cytometry: monitoring single cell signaling events. Cytometry A. 2003; 55(2):61-70. DOI: 10.1002/cyto.a.10072. View

Kronenberg M, Rudensky A . Regulation of immunity by self-reactive T cells. Nature. 2005; 435(7042):598-604. DOI: 10.1038/nature03725. View

Krutzik P, Crane J, Clutter M, Nolan G . High-content single-cell drug screening with phosphospecific flow cytometry. Nat Chem Biol. 2007; 4(2):132-42. DOI: 10.1038/nchembio.2007.59. View

Almeida A, Zaragoza B, Freitas A . Indexation as a novel mechanism of lymphocyte homeostasis: the number of CD4+CD25+ regulatory T cells is indexed to the number of IL-2-producing cells. J Immunol. 2006; 177(1):192-200. DOI: 10.4049/jimmunol.177.1.192. View

Setoguchi R, Hori S, Takahashi T, Sakaguchi S . Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005; 201(5):723-35. PMC: 2212841. DOI: 10.1084/jem.20041982. View

Sakaguchi S . Regulatory T cells: key controllers of immunologic self-tolerance. Cell. 2000; 101(5):455-8. DOI: 10.1016/s0092-8674(00)80856-9. View

Khoruts A, Mondino A, Pape K, Reiner S, Jenkins M . A natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism. J Exp Med. 1998; 187(2):225-36. PMC: 2212094. DOI: 10.1084/jem.187.2.225. View

Yu C, Mahdi R, Ebong S, Vistica B, Gery I, Egwuagu C . Suppressor of cytokine signaling 3 regulates proliferation and activation of T-helper cells. J Biol Chem. 2003; 278(32):29752-9. DOI: 10.1074/jbc.M300489200. View

Belkaid Y . Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol. 2007; 7(11):875-88. DOI: 10.1038/nri2189. View

10.

Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo M . CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007; 8(12):1353-62. DOI: 10.1038/ni1536. View

11.

Suvas S, Kumaraguru U, Pack C, Lee S, Rouse B . CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med. 2003; 198(6):889-901. PMC: 2194203. DOI: 10.1084/jem.20030171. View

12.

Fontenot J, Rasmussen J, Williams L, Dooley J, Farr A, Rudensky A . Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005; 22(3):329-41. DOI: 10.1016/j.immuni.2005.01.016. View

13.

Yoshimura A, Naka T, Kubo M . SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007; 7(6):454-65. DOI: 10.1038/nri2093. View

14.

Krutzik P, Hale M, Nolan G . Characterization of the murine immunological signaling network with phosphospecific flow cytometry. J Immunol. 2005; 175(4):2366-73. DOI: 10.4049/jimmunol.175.4.2366. View

15.

Pillemer B, Xu H, Oriss T, Qi Z, Ray A . Deficient SOCS3 expression in CD4+CD25+FoxP3+ regulatory T cells and SOCS3-mediated suppression of Treg function. Eur J Immunol. 2007; 37(8):2082-9. DOI: 10.1002/eji.200737193. View

16.

Irish J, Hovland R, Krutzik P, Perez O, Bruserud O, Gjertsen B . Single cell profiling of potentiated phospho-protein networks in cancer cells. Cell. 2004; 118(2):217-28. DOI: 10.1016/j.cell.2004.06.028. View

17.

Gett A, Sallusto F, Lanzavecchia A, Geginat J . T cell fitness determined by signal strength. Nat Immunol. 2003; 4(4):355-60. DOI: 10.1038/ni908. View

18.

Cornish A, Chong M, Davey G, Darwiche R, Nicola N, Hilton D . Suppressor of cytokine signaling-1 regulates signaling in response to interleukin-2 and other gamma c-dependent cytokines in peripheral T cells. J Biol Chem. 2003; 278(25):22755-61. DOI: 10.1074/jbc.M303021200. View

19.

Lund J, Hsing L, Pham T, Rudensky A . Coordination of early protective immunity to viral infection by regulatory T cells. Science. 2008; 320(5880):1220-4. PMC: 2519146. DOI: 10.1126/science.1155209. View

20.

Williams M, Tyznik A, Bevan M . Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature. 2006; 441(7095):890-3. PMC: 2776073. DOI: 10.1038/nature04790. View