RESEARCH ARTICLE

Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival

  • Dan Tong 1 ,
  • Li Zhang 1 ,
  • Fei Ning 1 ,
  • Ying Xu 1 ,
  • Xiaoyu Hu , 1 ,
  • Yan Shi , 1,2
Expand
  • 1. Tsinghua Institute for Immunology and Department of Basic Medical Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
  • 2. Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, Canada

Received date: 05 Aug 2019

Accepted date: 18 Sep 2019

Published date: 15 Feb 2020

Copyright

2019 The Author(s)

Abstract

Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vitro.

Cite this article

Dan Tong , Li Zhang , Fei Ning , Ying Xu , Xiaoyu Hu , Yan Shi . Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival[J]. Protein & Cell, 2020 , 11(2) : 108 -123 . DOI: 10.1007/s13238-019-00662-0

1
Audic S, Claverie JM (1997) The significance of digital gene expression profiles. Genome Res 7:986–995

DOI

2
Bell EB, Westermann J (2008) CD4 memory T cells on trial: immunological memory without a memory T cell. Trends Immunol 29:405–411

DOI

3
Choi UY, Kang J-S, Hwang YS, Kim Y-J(2015) Oligoadenylate synthase-like (OASL) proteins: dual functions and associations with diseases. Exp Mol Med 47:e144

DOI

4
Ciabattini A, Pettini E, Andersen P, Pozzi G, Medaglini D (2008) Primary activation of antigen-specific naive CD4+ and CD8+ T cells following intranasal vaccination with recombinant bacteria. Infect Immun 76:5817–5825

DOI

5
Feau S, Arens R, Togher S, Schoenberger SP (2011) Autocrine IL-2 is required for secondary population expansion of CD8(+) memory T cells. Nat Immunol 12:908–913

DOI

6
Gasper DJ, Tejera MM, Suresh M (2014) CD4 T-cell memory generation and maintenance. Crit Rev Immunol 34:121–146

DOI

7
Goodridge HS, Simmons RM, Underhill DM (2007) Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells. J Immunol 178:3107–3115

DOI

8
Granucci F, Vizzardelli C, Pavelka N, Feau S, Persico M, Virzi E, Rescigno M, Moro G, Ricciardi-Castagnoli P(2001) Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nat Immunol 2:882–888

DOI

9
Granucci F, Feau S, Angeli V, Trottein F, Ricciardi-Castagnoli P (2003) Early IL-2 production by mouse dendritic cells is the result of microbial-induced priming. J Immunol 170:5075–5081

DOI

10
Heink S, Yogev N, Garbers C, Herwerth M, Aly L, Gasperi C, Husterer V,Croxford AL, Moller-Hackbarth K, Bartsch HS (2017) Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat Immunol 18:74–85

DOI

11
Kakiuchi T, Tamura T, Gyotoku Y, Nariuchi H (1991) IL-2 production by B cells stimulated with a specific antigen. Cell Immunol 138:207–215

DOI

12
Kalia V,Sarkar S, Subramaniam S, Haining WN, Smith KA, Ahmed R(2010) Prolonged interleukin-2Ralpha expression on virusspecific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32:91–103

DOI

13
Kieper WC, Burghardt JT, Surh CD (2004) A role for TCR affinity in regulating naive T cell homeostasis. J Immunol 172:40–44

DOI

14
Liao W, Lin J-X, Leonard WJ (2013) Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38:13–25

DOI

15
MacLeod MKL, Clambey ET, Kappler JW, Marrack P (2009) CD4 memory T cells: what are they and what can they do? Semin Immunol 21:53–61

DOI

16
McKinstry KK, Strutt TM, Bautista B, Zhang W, Kuang Y, Cooper AM, Swain SL (2014) Effector CD4 T-cell transition to memory requires late cognate interactions that induce autocrine IL-2. Nat Commun 5:5377

DOI

17
Park C, Li S, Cha E, Schindler C (2000) Immune response in Stat2 knockout mice. Immunity 13:795–804

DOI

18
Raeber ME, Zurbuchen Y, Impellizzieri D, Boyman O (2018) The role of cytokines in T-cell memory in health and disease. Immunol Rev 283:176–193

DOI

19
Ross SH, Cantrell DA (2018) Signaling and Function of Interleukin-2 in T Lymphocytes. Annu Rev Immunol 36:411–433

DOI

20
Schartz NE, Chaput N, Taieb J, Bonnaventure P, Trebeden-Negre H, Terme M, Menard C, Lebbe C, Schimpl A, Ardouin P (2005) IL-2 production by dendritic cells is not critical for the activation of cognate and innate effectors in draining lymph nodes. Eur J Immunol 35:2840–2850

DOI

21
Smith KA (2015) Commentary: the Interleukin-2 Tcell system: a new cell growth model. Front Immunol 6:414

DOI

22
Sojka DK, Bruniquel D,Schwartz RH, Singh NJ (2004) IL-2 secretion by CD4+ T cells in vivo is rapid, transient, and influenced by TCR-specific competition. J Immunol 172:6136–6143

DOI

23
Spolski R, Gromer D, Leonard WJ (2017) The γ (c) family of cytokines: fine-tuning signals from IL-2 and IL-21 in the regulation of the immune response. F1000Research 6:1872

DOI

24
Steiner QG, Otten LA, Hicks MJ, Kaya G, Grosjean F, Saeuberli E, Lavanchy C, Beermann F, McClain KL, Acha-Orbea H (2008) In vivo transformation of mouse conventional CD8alpha+ dendritic cells leads to progressive multisystem histiocytosis. Blood 111:2073–2082

DOI

25
Tanchot C, Lemonnier FA, Perarnau B, Freitas AA, Rocha B (1997) Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276:2057–2062

DOI

26
Tian Y, Meng L, Zhang Y (2017) Epigenetic regulation of dendritic cell development and function. Cancer J (Sudbury, Mass) 23:302–307

DOI

27
Venuta S, Mertelsmann R, Welte K, Feldman SP, Wang CY, Moore MA (1983) Production and regulation of interleukin-2 in human lymphoblastic leukemias studied with T-cell monoclonal antibodies. Blood 61:781–789

DOI

28
Villarino AV, Tato CM, Stumhofer JS, Yao Z, Cui YK, Hennighausen L, O’Shea JJ, Hunter CA (2007) Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals. J Exp Med 204:65–71

DOI

29
von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B (2003) STRING: a database of predicted functional associations between proteins. Nucleic Acids Res 31:258–261

DOI

30
Williams MA, Tyznik AJ, Bevan MJ (2006) Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 441:890–893

DOI

31
Wuest SC, Edwan J, Martin JF, Han S, Perry JSA, Cartagena CM, Matsuura E, Maric D, Waldmann TA, Bielekova B (2011) A vital role for IL-2 trans-presentation in DC-mediated T cell activation in humans as revealed by daclizumab therapy. Nat Med 17:604–609

DOI

32
Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275:1129–1132

DOI

33
Zhao C, Collins MN, Hsiang TY, Krug RM (2013) Interferon-induced ISG15 pathway: an ongoing virus-host battle. Trends Microbiol 21:181–186

DOI

34
Zhou MJ, Chen FZ, Chen HC, Wan XX, Zhou X, Fang Q, Zhang DZ (2017) ISG15 inhibits cancer cell growth and promotes apoptosis. Int J Mol Med 39:446–452

DOI

Outlines

/