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Apoptotic cell-treated dendritic cells induce immune tolerance by specifically inhibiting development of CD4+ effector memory T cells

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Abstract

CD4+ memory T cells play an important role in induction of autoimmunity and chronic inflammatory responses; however, regulatory mechanisms of CD4+ memory T cell-mediated inflammatory responses are poorly understood. Here we show that apoptotic cell-treated dendritic cells inhibit development and differentiation of CD4+ effector memory T cells in vitro and in vivo. Simultaneously, intravenous transfer of apoptotic T cell-induced tolerogenic dendritic cells can block development of experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the central nervous system in C57 BL/6J mouse. Our results imply that it is effector memory CD4+ T cells, not central memory CD4+ T cells, which play a major role in chronic inflammatory responses in mice with EAE. Intravenous transfer of tolerogenic dendritic cells induced by apoptotic T cells leads to immune tolerance by specifically blocking development of CD4+ effector memory T cells compared with results of EAE control mice. These results reveal a new mechanism of apoptotic cell-treated dendritic cell-mediated immune tolerance in vivo.

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Abbreviations

CD:

Cluster of differentiation

DC:

Dendritic cell

EAE:

Experimental autoimmune encephalomyelitis

FACS:

Fluorescence-activated cell sorting

FCS:

Fetal calf serum

FoxP3:

Forkhead box P3

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

IL:

Interleukin

MOG:

Myelin oligodendrocyte glycoprotein

MS:

Multiple sclerosis

PBS:

Phosphate-buffered saline

SD:

Standard deviation

SEM:

Standard error of arithmetic mean

TCM :

Central memory T cell

TCR:

T cell receptor

TEM :

Effector memory T cell

TRM :

Tissue-resident memory T cell

References

  1. Sattler A, Wagner U, Rossol M, Sieper J, Wu P, Krause A, Schmidt WA, Radmer S, Kohler S, Romagnani C, Thiel A. Cytokine-induced human IFN-gamma-secreting effector-memory Th cells in chronic autoimmune inflammation. Blood. 2009;113:1948–56.

    Article  PubMed  CAS  Google Scholar 

  2. Eyrich M, Croner T, Leiler C, Lang P, Bader P, Klingebiel T, Niethammer D, Schlegel PG. Distinct contributions of CD4(+) and CD8(+) naive and memory T-cell subsets to overall T-cell-receptor repertoire complexity following transplantation of T-cell-depleted CD34-selected hematopoietic progenitor cells from unrelated donors. Blood. 2002;100:1915–8.

    Article  PubMed  CAS  Google Scholar 

  3. Roberts AD, Ely KH, Woodland DL. Differential contributions of central and effector memory T cells to recall responses. J Exp Med. 2005;202:123–33.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. Booth JS, Toapanta FR, Salerno-Goncalves R, Patil S, Kader HA, Safta AM, Czinn SJ, Greenwald BD, Sztein MB. Characterization and functional properties of gastric tissue-resident memory T cells from children, adults, and the elderly. Front Immunol. 2014;5:294.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Mueller SN, Gebhardt T, Carbone FR, Heath WR. Memory T cell subsets, migration patterns, and tissue residence. Annu Rev Immunol. 2013;31:137–61.

    Article  PubMed  CAS  Google Scholar 

  6. Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, Vega-Ramos J, Lauzurica P, Mueller SN, Stefanovic T, Tscharke DC, Heath WR, Inouye M, Carbone FR, Gebhardt T. The developmental pathway for CD103(+)CD8 + tissue-resident memory T cells of skin. Nat Immunol. 2013;14:1294–301.

    Article  PubMed  CAS  Google Scholar 

  7. Xie J, Lin YK, Wang K, Che B, Li JQ, Xu X, Han F, Liang DH. Induced immune tolerance of autoantigen loaded immature dendritic cells in homogenic lupus mice. Genet Mol Res GMR. 2014;13:1251–62.

    Article  PubMed  CAS  Google Scholar 

  8. Mbongue J, Nicholas D, Firek A, Langridge W. The role of dendritic cells in tissue-specific autoimmunity. J Immunol Res. 2014;2014:857143.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Ganguly D, Haak S, Sisirak V, Reizis B. The role of dendritic cells in autoimmunity. Nat Rev Immunol. 2013;13:566–77.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Hassan I, Brendel C, Zielke A, Burchert A, Danila R. Immune regulatory plasmacytoid dendritic cells selectively accumulate in perithyroidal lymph nodes of patients with Graves disease: implications for the understanding of autoimmunity. Rev Med Chir Soc Med Nat Iasi. 2013;117:46–51.

    PubMed  CAS  Google Scholar 

  11. Manh TP, Alexandre Y, Baranek T, Crozat K, Dalod M. Plasmacytoid, conventional, and monocyte-derived dendritic cells undergo a profound and convergent genetic reprogramming during their maturation. Eur J Immunol. 2013;43:1706–15.

    Article  PubMed  CAS  Google Scholar 

  12. Froidure A, Shen C, Gras D, Van Snick J, Chanez P, Pilette C. Myeloid dendritic cells are primed in allergic asthma for thymic stromal lymphopoietin-mediated induction of Th2 and Th9 responses. Allergy. 2014;69:1068–76.

    Article  PubMed  CAS  Google Scholar 

  13. Kim SJ, Diamond B. Modulation of tolerogenic dendritic cells and autoimmunity. Semin Cell Dev Biol. 2014;S1084–9521(14):00091–3.

    Google Scholar 

  14. Alonso MN, Gregorio JG, Davidson MG, Gonzalez JC, Engleman EG. Depletion of inflammatory dendritic cells with anti-CD209 conjugated to saporin toxin. Immunol Res. 2014;58:374–7.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Torres-Aguilar H, Sanchez-Torres C, Jara LJ, Blank M, Shoenfeld Y. IL-10/TGF-beta-treated dendritic cells, pulsed with insulin, specifically reduce the response to insulin of CD4+ effector/memory T cells from type 1 diabetic individuals. J Clin Immunol. 2010;30:659–68.

    Article  PubMed  CAS  Google Scholar 

  16. Nikolic T, Roep BO. Regulatory multitasking of tolerogenic dendritic cells—lessons taken from vitamin d3-treated tolerogenic dendritic cells. Front Immunol. 2013;4:113.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Wu C, Zhang Y, Jiang Y, Wang Q, Long Y, Wang C, Cao X, Chen G. Apoptotic cell administration enhances pancreatic islet engraftment by induction of regulatory T cells and tolerogenic dendritic cells. Cell Mol Immunol. 2013;10:393–402.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  18. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711.

    Article  PubMed  CAS  Google Scholar 

  19. Mastorodemos V, Ioannou M, Verginis P. Cell-based modulation of autoimmune responses in multiple sclerosis and experimental autoimmune encephalomyelitis: therapeutic implications. NeuroImmunoModulation. 2015;22(3):181–95.

    Article  PubMed  CAS  Google Scholar 

  20. Yeh WI, McWilliams IL, Harrington LE. Autoreactive Tbet-positive CD4 T cells develop independent of classic Th1 cytokine signaling during experimental autoimmune encephalomyelitis. J Immunol. 2011;187:4998–5006.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Zhou F, Lauretti E, di Meco A, Ciric B, Gonnella P, Zhang GX, Rostami A. Intravenous transfer of apoptotic cell-treated dendritic cells leads to immune tolerance by blocking Th17 cell activity. Immunobiology. 2013;218:1069–76.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Zhou F, Ciric B, Zhang GX, Rostami A. Immune tolerance induced by intravenous transfer of immature dendritic cells via up-regulating numbers of suppressive IL-10(+) IFN-gamma(+)-producing CD4(+) T cells. Immunol Res. 2013;56:1–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. Zhou F, Ciric B, Li H, Yan Y, Li K, Cullimore M, Lauretti E, Gonnella P, Zhang GX, Rostami A. IL-10 deficiency blocks the ability of LPS to regulate expression of tolerance-related molecules on dendritic cells. Eur J Immunol. 2012;42:1449–58.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Zhou F, Ciric B, Zhang GX, Rostami A. Immunotherapy using lipopolysaccharide-stimulated bone marrow-derived dendritic cells to treat experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2014;178:447–58.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Torres-Aguilar H, Aguilar-Ruiz SR, Gonzalez-Perez G, Munguia R, Bajana S, Meraz-Rios MA, Sanchez-Torres C. Tolerogenic dendritic cells generated with different immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4+ T cells. J immunol. 2010;184:1765–75.

    Article  PubMed  CAS  Google Scholar 

  26. Torres-Aguilar H, Blank M, Kivity S, Misgav M, Luboshitz J, Pierangeli SS, Shoenfeld Y. Tolerogenic dendritic cells inhibit antiphospholipid syndrome derived effector/memory CD4(+) T cell response to beta2GPI. Ann Rheum Dis. 2012;71:120–8.

    Article  PubMed  CAS  Google Scholar 

  27. Nasreen M, Waldie TM, Dixon CM, Steptoe RJ. Steady-state antigen-expressing dendritic cells terminate CD4+ memory T-cell responses. Eur J Immunol. 2010;40:2016–25.

    Article  PubMed  CAS  Google Scholar 

  28. Zhou F. Molecular mechanisms of IFN-gamma to up-regulate MHC class I antigen processing and presentation. Int Rev Immunol. 2009;28:239–60.

    Article  PubMed  CAS  Google Scholar 

  29. Perry LL, Feilzer K, Caldwell HD. Immunity to Chlamydia trachomatis is mediated by T helper 1 cells through IFN-gamma-dependent and -independent pathways. J Immunol. 1997;158:3344–52.

    PubMed  CAS  Google Scholar 

  30. Olson NC, Doyle MF, Jenny NS, Huber SA, Psaty BM, Kronmal RA, Tracy RP. Decreased naive and increased memory CD4(+) T cells are associated with subclinical atherosclerosis: the multi-ethnic study of atherosclerosis. PLoS One. 2013;8:e71498.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  31. Oh HM, Yu CR, Lee Y, Chan CC, Maminishkis A, Egwuagu CE. Autoreactive memory CD4+ T lymphocytes that mediate chronic uveitis reside in the bone marrow through STAT3-dependent mechanisms. J Immunol. 2011;187:3338–46.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  32. Haines CJ, Chen Y, Blumenschein WM, Jain R, Chang C, Joyce-Shaikh B, Porth K, Boniface K, Mattson J, Basham B, Anderton SM, McClanahan TK, Sadekova S, Cua DJ, McGeachy MJ. Autoimmune memory T helper 17 cell function and expansion are dependent on interleukin-23. Cell Rep. 2013;3:1378–88.

    Article  PubMed  CAS  Google Scholar 

  33. Elyaman W, Kivisakk P, Reddy J, Chitnis T, Raddassi K, Imitola J, Bradshaw E, Kuchroo VK, Yagita H, Sayegh MH, Khoury SJ. Distinct functions of autoreactive memory and effector CD4+ T cells in experimental autoimmune encephalomyelitis. Am J Pathol. 2008;173:411–22.

    Article  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Thomas Jefferson University, 901 Walnut Street, Philadelphia, PA, 19107, USA

    Fang Zhou, Guang-Xian Zhang & Abdolmohamad Rostami

  2. Laboratory of Liver Cancer Immunotherapy, Greenslopes Private Hospital, School of Medicine, University of Queensland, Greenslopes, Brisbane, QLD, 4120, Australia

    Fang Zhou

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  1. Fang Zhou
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Correspondence to Abdolmohamad Rostami.

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Zhou, F., Zhang, GX. & Rostami, A. Apoptotic cell-treated dendritic cells induce immune tolerance by specifically inhibiting development of CD4+ effector memory T cells. Immunol Res 64, 73–81 (2016). https://doi.org/10.1007/s12026-015-8676-7

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