Skip to main content
SpringerLink
Log in

Role of Regulatory T cells in Epilepsy

  • Chapter
  • First Online:
Inflammation and Epilepsy: New Vistas

Part of the book series: Progress in Inflammation Research ((PIR,volume 88))

Abstract

In the past two decades, there has been increasing interest in the potential contributions of immune activation and neural inflammation to the pathogenesis of seizures and epilepsies. Studies have focused on the contribution of antibody-mediated encephalitis as well as pro-inflammatory mediators produced by brain-resident glial cells to the pathogenesis of epilepsy and seizure induction. Immune activation that leads to functional rewiring of the brain can be both the cause and the consequence of seizures. The immune response, however, is a process tightly controlled by a system of checks and balances to prevent aberrant inflammatory damage. The role of regulatory immune cells that suppress overt immune activation has been largely unexplored in epileptogenesis and seizure control. In this review, we discuss experimental data generated in our laboratory to examine the role of regulatory immune cells in seizure modulation and epileptogenesis. Specifically, we focus on the emerging knowledge of CD4+FoxP3+ regulatory T cells (Tregs) in neurological disorders, recruitment of thymus-derived natural Tregs (tTregs) to the central nervous system (CNS), generation of peripherally derived antigen-specific Tregs (pTregs), Treg markers, and the immunosuppressive mechanisms of Tregs. We discuss the interaction between immune regulatory cells and inflammation-driven effector cells in the regulation of neural inflammation to suppress excessive immune responses deleterious to the host and maintenance of immune homeostasis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

Ab::

antibody

APC::

antigen-presenting cells

BBB::

blood-brain barrier

CD127::

IL-7 receptor alpha chain

CNS::

central nervous system

CSF::

cerebral spinal fluid

CTL::

cytotoxic T lymphocyte

CTLA-4::

cytotoxic T lymphocytes antigen-4

DC::

dendritic cells

FoxP3::

forkhead box P3

FR4::

folate receptor 4

GARP::

glycoprotein A repetitions predominant

GFP::

green fluorescent protein

GITR::

glucocorticoid-induced tumor necrosis factor receptor

ICOS::

inducible co-stimulator

IL-10::

interleukin-10

IMP::

immune-modifying nanoparticle

iTreg::

induced regulatory T cells

IPEX::

immune dysregulation, polyendocrinopathy, enteropathy, and X-linked

KA::

kainic acid

LAG-3::

lymphocyte activation antigen-3

LAP::

latency-associated peptide

MHC::

major histocompatibility complex

mTOR::

mammalian target of rapamycin

NFAT::

nuclear factor of activated T cells

NF-kB::

nuclear factor-kB

NOD-Rag::

Non-obese diabetic–recombination activating gene

PD-1::

programmed cell death-1

PI3K::

phosphatidylinositol-3-kinase

PLGA::

carboxylated poly(lactic-co-glycolic) acid

PTEN::

phosphatase and tensin homolog

pTregs::

peripherally derived regulatory T cells

S1P1::

sphingosine phosphate receptor 1

SCID::

severe combined immunodeficiency

Tconv::

conventional T cells

TCR::

T cell receptor

Teff::

effector T cells

TGF-β::

tumor necrosis factor-β

Tr1::

type 1 regulatory T cells

Tregs::

regulatory T cells

tTregs::

thymus-derived regulatory T cells

TSDR::

Treg-specific demethylation region

References

  1. Cornford EM. Epilepsy and the blood brain barrier: endothelial cell responses to seizures. Adv Neurol. 1999;79:845–62. PubMed PMID: 10514868

    CAS  PubMed  Google Scholar 

  2. Stolp HB, Dziegielewska KM. Review: role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases. Neuropathol Appl Neurobiol. 2009;35(2):132–46. https://doi.org/10.1111/j.1365-2990.2008.01005.x. PubMed PMID: 19077110

    Article  CAS  PubMed  Google Scholar 

  3. Sardi F, Fassina L, Venturini L, Inguscio M, Guerriero F, Rolfo E, Ricevuti G. Alzheimer’s disease, autoimmunity and inflammation. The good, the bad and the ugly. Autoimmun Rev. 2011;11(2):149–53. https://doi.org/10.1016/j.autrev.2011.09.005. PubMed PMID: 21996556

    Article  CAS  PubMed  Google Scholar 

  4. Xu D, Miller SD, Koh S. Immune mechanisms in epileptogenesis. Front Cell Neurosci. 2013;7:195. https://doi.org/10.3389/fncel.2013.00195. PubMed PMID: 24265605; PMCID: PMC3821015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brusko TM, Putnam AL, Bluestone JA. Human regulatory t cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev. 2008;223:371–90. https://doi.org/10.1111/j.1600-065X.2008.00637.x. PubMed PMID: 18613848

    Article  CAS  PubMed  Google Scholar 

  6. Pot C, Apetoh L, Kuchroo VK. Type 1 regulatory t cells (tr1) in autoimmunity. Semin Immunol. 2011;23(3):202–8. https://doi.org/10.1016/j.smim.2011.07.005. PubMed PMID: 21840222; PMCID: PMC3178065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gravano DM, Hoyer KK. Promotion and prevention of autoimmune disease by cd8+ t cells. J Autoimmun. 2013;45:68–79. https://doi.org/10.1016/j.jaut.2013.06.004. PubMed PMID: 23871638

    Article  CAS  PubMed  Google Scholar 

  8. Pennati A, Ng S, Wu Y, Murphy JR, Deng J, Rangaraju S, Asress S, Blanchfield JL, Evavold B, Galipeau J. Regulatory b cells induce formation of il-10-expressing t cells in mice with autoimmune neuroinflammation. J Neurosci. 2016;36(50):12598–610. https://doi.org/10.1523/JNEUROSCI.1994-16.2016. PubMed PMID: 27821578; PMCID: PMC5157105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mann MK, Ray A, Basu S, Karp CL, Dittel BN. Pathogenic and regulatory roles for b cells in experimental autoimmune encephalomyelitis. Autoimmunity. 2012;45(5):388–99. https://doi.org/10.3109/08916934.2012.665523. PubMed PMID: 22443691; PMCID: PMC3639139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kivisakk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, Wu L, Baekkevold ES, Lassmann H, Staugaitis SM, Campbell JJ, Ransohoff RM. Human cerebrospinal fluid central memory cd4+ t cells: evidence for trafficking through choroid plexus and meninges via p-selectin. Proc Natl Acad Sci U S A. 2003;100(14):8389–94. PubMed PMID: 12829791

    PubMed  PubMed Central  Google Scholar 

  11. Engelhardt B, Ransohoff RM. The ins and outs of t-lymphocyte trafficking to the cns: anatomical sites and molecular mechanisms. Trends Immunol. 2005;26(9):485–95. PubMed PMID: 16039904

    CAS  PubMed  Google Scholar 

  12. Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006;9(2):268–75. PubMed PMID: 16415867

    CAS  PubMed  Google Scholar 

  13. Wolf SA, Steiner B, Akpinarli A, Kammertoens T, Nassenstein C, Braun A, Blankenstein T, Kempermann G. Cd4-positive t lymphocytes provide a neuroimmunological link in the control of adult hippocampal neurogenesis. J Immunol. 2009;182(7):3979–84. PubMed PMID: 19299695

    CAS  PubMed  Google Scholar 

  14. Radjavi A, Smirnov I, Kipnis J. Brain antigen-reactive cd4+ t cells are sufficient to support learning behavior in mice with limited t cell repertoire. Brain Behav Immun. 2014;35:58–63. PubMed PMID: 24012647

    CAS  PubMed  Google Scholar 

  15. Rattazzi L, Piras G, Ono M, Deacon R, Pariante CM, D’Acquisto F. Cd4(+) but not cd8(+) t cells revert the impaired emotional behavior of immunocompromised rag-1-deficient mice. Transl Psychiatry. 2013;3:e280. PubMed PMID: 23838891

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A. Induced regulatory t cells: their development, stability, and applications. Trends Immunol. 2016;37(11):803–11. PubMed PMID: 27623114

    CAS  PubMed  Google Scholar 

  17. Zattoni M, Mura ML, Deprez F, Schwendener RA, Engelhardt B, Frei K, Fritschy JM. Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. J Neurosci. 2011;31(11):4037–50. PubMed PMID: 21411646

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE, Kolbeck R, Hoppe E, Oropeza-Wekerle RL, Bartke I, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R. Activated human t cells, b cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med. 1999;189(5):865–70. PubMed PMID: 10049950

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Vieira ELM, de Oliveira GNM, Lessa JMK, Goncalves AP, Oliveira ACP, Bauer ME, Sander JW, Cendes F, Teixeira AL. Peripheral leukocyte profile in people with temporal lobe epilepsy reflects the associated proinflammatory state. Brain Behav Immun. 2016;53:123–30. PubMed PMID: 26640228

    CAS  PubMed  Google Scholar 

  20. Xu D, Robinson AP, Ishii T, Duncan DS, Alden TD, Goings GE, Ifergan I, Podojil JR, Penaloza-MacMaster P, Kearney JA, Swanson GT, Miller SD, Koh S. Peripherally derived t regulatory and gammadelta t cells have opposing roles in the pathogenesis of intractable pediatric epilepsy. J Exp Med. 2018;215(4):1169–86. https://doi.org/10.1084/jem.20171285. PubMed PMID: 29487082; PMCID: PMC5881465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Faria AM, Weiner HL. Oral tolerance: therapeutic implications for autoimmune diseases. Clin Dev Immunol. 2006;13(2–4):143–57. PubMed PMID: 17162357

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Jadidi-Niaragh F, Mirshafiey A. Regulatory t-cell as orchestra leader in immunosuppression process of multiple sclerosis. Immunopharmacol Immunotoxicol. 2011;33(3):545–67. PubMed PMID: 21284556

    CAS  PubMed  Google Scholar 

  23. He F, Balling R. The role of regulatory t cells in neurodegenerative diseases. Wiley Interdiscip Rev Syst BiolMed. 2013;5(2):153–80. PubMed PMID: 22899644

    CAS  Google Scholar 

  24. Walsh JT, Kipnis J. Regulatory t cells in cns injury: the simple, the complex and the confused. Trends Mol Med. 2011;17(10):541–7. PubMed PMID: 21741881

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL. Neuroprotective activities of cd4+cd25+ regulatory t cells in an animal model of Parkinson’s disease. J Leukoc Biol. 2007;82(5):1083–94. PubMed PMID: 17675560

    CAS  PubMed  Google Scholar 

  26. Kohm AP, Carpentier PA, Anger HA, Miller SD. Cutting edge: Cd4+cd25+ regulatory t cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol. 2002;169(9):4712–6. PubMed PMID: 12391178

    CAS  PubMed  Google Scholar 

  27. Getts DR, Terry RL, Getts MT, Deffrasnes C, Muller M, van Vreden C, Ashhurst TM, Chami B, McCarthy D, Wu H, Ma J, Martin A, Shae LD, Witting P, Kansas GS, Kuhn J, Hafezi W, Campbell IL, Reilly D, Say J, Brown L, White MY, Cordwell SJ, Chadban SJ, Thorp EB, Bao S, Miller SD, King NJ. Therapeutic inflammatory monocyte modulation using immune-modifying microparticles. Sci Transl Med. 2014;6(219):219ra217. PubMed PMID: 24431111

    Google Scholar 

  28. Getts DR, Shea LD, Miller SD, King NJ. Harnessing nanoparticles for immune modulation. Trends Immunol. 2015;36(7):419–27. PubMed PMID: 26088391

    CAS  PubMed  PubMed Central  Google Scholar 

  29. McCarthy DP, Hunter ZN, Chackerian B, Shea LD, Miller SD. Targeted immunomodulation using antigen-conjugated nanoparticles. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2014;6(3):298–315. PubMed PMID: 24616452

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Xu D, Prasad S, Miller SD. Inducing immune tolerance: a focus on type 1 diabetes mellitus. Diabetes Manag (Lond). 2013;3(5):415–26. PubMed PMID: 24505231

    CAS  PubMed  Google Scholar 

  31. Gershon RK. A disquisition on suppressor t cells. Transplant Rev. 1975;26:170–85. PubMed PMID: 1101469

    CAS  PubMed  Google Scholar 

  32. Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology. 1970;18(5):723–37. PubMed PMID: 4911896

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Gershon RK, Kondo K. Infectious immunological tolerance. Immunology. 1971;21(6):903–14. PubMed PMID: 4943147

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Okumura K, Herzenberg LA, Murphy DB, McDevitt HO, Herzenberg LA. Selective expression of h-2 (i-region) loci controlling determinants on helper and suppressor t lymphocytes. J Exp Med. 1976;144(3):685–98. PubMed PMID: 1085337

    CAS  PubMed  Google Scholar 

  35. Murphy DB, Herzenberg LA, Okumura K, Herzenberg LA, McDevitt HO. A new i subregion (i-j) marked by a locus (ia-4) controlling surface determinants on suppressor t lymphocytes. J Exp Med. 1976;144(3):699–712. PubMed PMID: 1085338

    CAS  PubMed  Google Scholar 

  36. Kobori JA, Strauss E, Minard K, Hood L. Molecular analysis of the hotspot of recombination in the murine major histocompatibility complex. Science (New York, NY). 1986;234(4773):173–9. PubMed PMID: 3018929

    CAS  Google Scholar 

  37. Kronenberg M, Steinmetz M, Kobori J, Kraig E, Kapp JA, Pierce CW, Sorensen CM, Suzuki G, Tada T, Hood L. Rna transcripts for i-j polypeptides are apparently not encoded between the i-a and i-e subregions of the murine major histocompatibility complex. Proc Natl Acad Sci U S A. 1983;80(18):5704–8. PubMed PMID: 6193520

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated t cells expressing il-2 receptor alpha-chains (cd25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151–64. PubMed PMID: 7636184

    CAS  PubMed  Google Scholar 

  39. Powrie F, Leach MW, Mauze S, Caddle LB, Coffman RL. Phenotypically distinct subsets of cd4+ t cells induce or protect from chronic intestinal inflammation in c. B-17 scid mice. Int. Immunology. 1993;5(11):1461–71. PubMed PMID: 7903159

    CAS  Google Scholar 

  40. Powrie F, Mason D. Ox-22high cd4+ t cells induce wasting disease with multiple organ pathology: prevention by the ox-22low subset. J Exp Med. 1990;172(6):1701–8. PubMed PMID: 2258700

    CAS  PubMed  Google Scholar 

  41. Thornton AM, Shevach EM. Cd4+cd25+ immunoregulatory t cells suppress polyclonal t cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998;188(2):287–96. PubMed PMID: 9670041

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Baud O, Goulet O, Canioni D, Le Deist F, Radford I, Rieu D, Dupuis-Girod S, Cerf-Bensussan N, Cavazzana-Calvo M, Brousse N, Fischer A, Casanova JL. Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (ipex) by allogeneic bone marrow transplantation. N Engl J Med. 2001;344(23):1758–62. PubMed PMID: 11396442

    CAS  PubMed  Google Scholar 

  43. Kobayashi I, Kawamura N, Okano M. A long-term survivor with the immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome. N Engl J Med. 2001;345(13):999–1000. PubMed PMID: 11575301

    CAS  PubMed  Google Scholar 

  44. Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and x-linked inheritance (ipex), a syndrome of systemic autoimmunity caused by mutations of foxp3, a critical regulator of t-cell homeostasis. Curr Opin Rheumatol. 2003;15(4):430–5. PubMed PMID: 12819471

    CAS  PubMed  Google Scholar 

  45. Bakke AC, Purtzer MZ, Wildin RS. Prospective immunological profiling in a case of immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (ipex). Clin Exp Immunol. 2004;137(2):373–8. PubMed PMID: 15270855

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18–20. PubMed PMID: 11137992

    CAS  PubMed  Google Scholar 

  47. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27(1):68–73. PubMed PMID: 11138001

    CAS  PubMed  Google Scholar 

  48. Roncador G, Brown PJ, Maestre L, Hue S, Martinez-Torrecuadrada JL, Ling KL, Pratap S, Toms C, Fox BC, Cerundolo V, Powrie F, Banham AH. Analysis of foxp3 protein expression in human cd4+cd25+ regulatory t cells at the single-cell level. Eur J Immunol. 2005;35(6):1681–91. PubMed PMID: 15902688

    CAS  PubMed  Google Scholar 

  49. Hori S, Nomura T, Sakaguchi S. Control of regulatory t cell development by the transcription factor foxp3. Science (New York, NY). 2003;299(5609):1057–61. PubMed PMID: 12522256

    CAS  Google Scholar 

  50. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of cd4+cd25+ regulatory t cells. Nat Immunol. 2003;4(4):330–6. PubMed PMID: 12612578

    CAS  PubMed  Google Scholar 

  51. Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF. Scurfin (foxp3) acts as a repressor of transcription and regulates t cell activation. J Biol Chem. 2001;276(40):37672–9. PubMed PMID: 11483607

    CAS  PubMed  Google Scholar 

  52. Bettelli E, Dastrange M, Oukka M. Foxp3 interacts with nuclear factor of activated t cells and nf-kappa b to repress cytokine gene expression and effector functions of t helper cells. Proc Natl Acad Sci U S A. 2005;102(14):5138–43. PubMed PMID: 15790681

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gavin MA, Torgerson TR, Houston E, DeRoos P, Ho WY, Stray-Pedersen A, Ocheltree EL, Greenberg PD, Ochs HD, Rudensky AY. Single-cell analysis of normal and foxp3-mutant human t cells: Foxp3 expression without regulatory t cell development. Proc Natl Acad Sci U S A. 2006;103(17):6659–64. PubMed PMID: 16617117

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Ono M, Shimizu J, Miyachi Y, Sakaguchi S. Control of autoimmune myocarditis and multiorgan inflammation by glucocorticoid-induced tnf receptor family-related protein(high), foxp3-expressing cd25+ and cd25- regulatory t cells. J Immunol. 2006;176(8):4748–56. PubMed PMID: 16585568

    CAS  PubMed  Google Scholar 

  55. Mahmud SA, Manlove LS, Schmitz HM, Xing Y, Wang Y, Owen DL, Schenkel JM, Boomer JS, Green JM, Yagita H, Chi H, Hogquist KA, Farrar MA. Costimulation via the tumor-necrosis factor receptor superfamily couples tcr signal strength to the thymic differentiation of regulatory t cells. Nat Immunol. 2014;15(5):473–81. PubMed PMID: 24633226

    CAS  PubMed  PubMed Central  Google Scholar 

  56. van Olffen RW, Koning N, van Gisbergen KP, Wensveen FM, Hoek RM, Boon L, Hamann J, van Lier RA, Nolte MA. Gitr triggering induces expansion of both effector and regulatory cd4+ t cells in vivo. J Immunol. 2009;182(12):7490–500. PubMed PMID: 19494272

    PubMed  Google Scholar 

  57. Lee BO, Jones JE, Peters CJ, Whitacre D, Frelin L, Hughes J, Kim WK, Milich DR. Identification of a unique double-negative regulatory t-cell population. Immunology. 2011;134(4):434–47. PubMed PMID: 22044159

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Zou Q, Wu B, Xue J, Fan X, Feng C, Geng S, Wang M, Wang B. Cd8+ treg cells suppress cd8+ t cell-responses by il-10-dependent mechanism during h5n1 influenza virus infection. Eur J Immunol. 2014;44(1):103–14. PubMed PMID: 24114149

    CAS  PubMed  Google Scholar 

  59. Mayer CT, Floess S, Baru AM, Lahl K, Huehn J, Sparwasser T. Cd8+ foxp3+ t cells share developmental and phenotypic features with classical cd4+ foxp3+ regulatory t cells but lack potent suppressive activity. Eur J Immunol. 2011;41(3):716–25. PubMed PMID: 21312192

    CAS  PubMed  Google Scholar 

  60. Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, Parmiani G, Belli F, Rivoltini L, Castelli C. Lag-3 expression defines a subset of cd4(+)cd25(high)foxp3(+) regulatory t cells that are expanded at tumor sites. J Immunol. 2010;184(11):6545–51. PubMed PMID: 20421648

    CAS  PubMed  Google Scholar 

  61. Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA. Role of lag-3 in regulatory t cells. Immunity. 2004;21(4):503–13. https://doi.org/10.1016/j.immuni.2004.08.010. PubMed PMID: 15485628

    Article  CAS  PubMed  Google Scholar 

  62. Maruhashi T, Okazaki IM, Sugiura D, Takahashi S, Maeda TK, Shimizu K, Okazaki T. Lag-3 inhibits the activation of cd4(+) t cells that recognize stable pmhcii through its conformation-dependent recognition of pmhcii. Nat Immunol. 2018;19(12):1415–26. PubMed PMID: 30349037

    CAS  PubMed  Google Scholar 

  63. Simpson TR, Quezada SA, Allison JP. Regulation of cd4 t cell activation and effector function by inducible costimulator (icos). Curr Opin Immunol. 2010;22(3):326–32. PubMed PMID: 20116985

    CAS  PubMed  Google Scholar 

  64. McAdam AJ, Chang TT, Lumelsky AE, Greenfield EA, Boussiotis VA, Duke-Cohan JS, Chernova T, Malenkovich N, Jabs C, Kuchroo VK, Ling V, Collins M, Sharpe AH, Freeman GJ. Mouse inducible costimulatory molecule (icos) expression is enhanced by cd28 costimulation and regulates differentiation of cd4+ t cells. J Immunol. 2000;165(9):5035–40. PubMed PMID: 11046032

    CAS  PubMed  Google Scholar 

  65. Ito T, Hanabuchi S, Wang YH, Park WR, Arima K, Bover L, Qin FX, Gilliet M, Liu YJ. Two functional subsets of foxp3+ regulatory t cells in human thymus and periphery. Immunity. 2008;28(6):870–80. PubMed PMID: 18513999

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Burmeister Y, Lischke T, Dahler AC, Mages HW, Lam KP, Coyle AJ, Kroczek RA, Hutloff A. Icos controls the pool size of effector-memory and regulatory t cells. J Immunol. 2008;180(2):774–82. PubMed PMID: 18178815

    CAS  PubMed  Google Scholar 

  67. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH. Pd-l1 regulates the development, maintenance, and function of induced regulatory t cells. J Exp Med. 2009;206(13):3015–29. PubMed PMID: 20008522

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, Klein-Hessling S, Serfling E, Hamann A, Huehn J. Epigenetic control of the foxp3 locus in regulatory t cells. PLoS Biol. 2007;5(2):e38. PubMed PMID: 17298177

    PubMed  PubMed Central  Google Scholar 

  69. Thangada S, Khanna KM, Blaho VA, Oo ML, Im DS, Guo C, Lefrancois L, Hla T. Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics. J Exp Med. 2010;207(7):1475–83. PubMed PMID: 20584883

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Edwards JP, Fujii H, Zhou AX, Creemers J, Unutmaz D, Shevach EM. Regulation of the expression of garp/latent tgf-beta1 complexes on mouse t cells and their role in regulatory t cell and th17 differentiation. J Immunol. 2013;190(11):5506–15. PubMed PMID: 23645881

    CAS  PubMed  Google Scholar 

  71. Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM. Garp (lrrc32) is essential for the surface expression of latent tgf-beta on platelets and activated foxp3+ regulatory t cells. Proc Natl Acad Sci U S A. 2009;106(32):13445–50. PubMed PMID: 19651619

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Stockis J, Colau D, Coulie PG, Lucas S. Membrane protein garp is a receptor for latent tgf-beta on the surface of activated human treg. Eur J Immunol. 2009;39(12):3315–22. PubMed PMID: 19750484

    CAS  PubMed  Google Scholar 

  73. Wang R, Wan Q, Kozhaya L, Fujii H, Unutmaz D. Identification of a regulatory t cell specific cell surface molecule that mediates suppressive signals and induces foxp3 expression. PLoS One. 2008;3(7):e2705. PubMed PMID: 18628982

    PubMed  PubMed Central  Google Scholar 

  74. Taams LS, Boot EP, van Eden W, Wauben MH. ‘Anergic’ t cells modulate the t-cell activating capacity of antigen-presenting cells. J Autoimmun. 2000;14(4):335–41. https://doi.org/10.1006/jaut.2000.0372. PubMed PMID: 10882060

    Article  CAS  PubMed  Google Scholar 

  75. Mempel TR, Pittet MJ, Khazaie K, Weninger W, Weissleder R, von Boehmer H, von Andrian UH. Regulatory t cells reversibly suppress cytotoxic t cell function independent of effector differentiation. Immunity. 2006;25(1):129–41. https://doi.org/10.1016/j.immuni.2006.04.015. PubMed PMID: 16860762

    Article  CAS  PubMed  Google Scholar 

  76. Eddahri F, Oldenhove G, Denanglaire S, Urbain J, Leo O, Andris F. Cd4+ cd25+ regulatory t cells control the magnitude of t-dependent humoral immune responses to exogenous antigens. Eur J Immunol. 2006;36(4):855–63. https://doi.org/10.1002/eji.200535500. PubMed PMID: 16511897

    Article  CAS  PubMed  Google Scholar 

  77. Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, Candeloro P, Belladonna ML, Bianchi R, Fioretti MC, Puccetti P. Ctla-4-ig regulates tryptophan catabolism in vivo. Nat Immunol. 2002;3(11):1097–101. https://doi.org/10.1038/ni846. PubMed PMID: 12368911

    Article  CAS  PubMed  Google Scholar 

  78. Oderup C, Cederbom L, Makowska A, Cilio CM, Ivars F. Cytotoxic t lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in cd4+ cd25+ regulatory t-cell-mediated suppression. Immunology. 2006;118(2):240–9. https://doi.org/10.1111/j.1365-2567.2006.02362.x. PubMed PMID: 16771859; PMCID: PMC1782280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Paust S, Lu L, McCarty N, Cantor H. Engagement of b7 on effector t cells by regulatory t cells prevents autoimmune disease. Proc Natl Acad Sci U S A. 2004;101(28):10398–403. https://doi.org/10.1073/pnas.0403342101. PubMed PMID: 15235129; PMCID: PMC478583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S. Foxp3+ natural regulatory t cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci U S A. 2008;105(29):10113–8. https://doi.org/10.1073/pnas.0711106105. PubMed PMID: 18635688; PMCID: PMC2481354

    Article  PubMed  PubMed Central  Google Scholar 

  81. Read S, Greenwald R, Izcue A, Robinson N, Mandelbrot D, Francisco L, Sharpe AH, Powrie F. Blockade of ctla-4 on cd4+cd25+ regulatory t cells abrogates their function in vivo. J Immunol. 2006;177(7):4376–83. https://doi.org/10.4049/jimmunol.177.7.4376. PubMed PMID: 16982872; PMCID: PMC6108417

    Article  CAS  PubMed  Google Scholar 

  82. Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA. Distinct roles of ctla-4 and tgf-beta in cd4+cd25+ regulatory t cell function. Eur J Immunol. 2004;34(11):2996–3005. https://doi.org/10.1002/eji.200425143. PubMed PMID: 15468055

    Article  CAS  PubMed  Google Scholar 

  83. Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, Naji A, Caton AJ. Thymic selection of cd4+cd25+ regulatory t cells induced by an agonist self-peptide. Nat Immunol. 2001;2(4):301–6. https://doi.org/10.1038/86302. PubMed PMID: 11276200

    Article  CAS  PubMed  Google Scholar 

  84. Pacholczyk R, Ignatowicz H, Kraj P, Ignatowicz L. Origin and t cell receptor diversity of foxp3+cd4+cd25+ t cells. Immunity. 2006;25(2):249–59. https://doi.org/10.1016/j.immuni.2006.05.016. PubMed PMID: 16879995

    Article  CAS  PubMed  Google Scholar 

  85. Pacholczyk R, Kern J, Singh N, Iwashima M, Kraj P, Ignatowicz L. Nonself-antigens are the cognate specificities of foxp3+ regulatory t cells. Immunity. 2007;27(3):493–504. https://doi.org/10.1016/j.immuni.2007.07.019. PubMed PMID: 17869133; PMCID: PMC2276657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA. In vitro-expanded antigen-specific regulatory t cells suppress autoimmune diabetes. J Exp Med. 2004;199(11):1455–65. https://doi.org/10.1084/jem.20040139. PubMed PMID: 15184499; PMCID: PMC2211775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hori S, Haury M, Coutinho A, Demengeot J. Specificity requirements for selection and effector functions of cd25+4+ regulatory t cells in anti-myelin basic protein t cell receptor transgenic mice. Proc Natl Acad Sci U S A. 2002;99(12):8213–8. https://doi.org/10.1073/pnas.122224799. PubMed PMID: 12034883; PMCID: PMC123047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Davidson TS, DiPaolo RJ, Andersson J, Shevach EM. Cutting edge: Il-2 is essential for tgf-beta-mediated induction of foxp3+ t regulatory cells. J Immunol. 2007;178(7):4022–6. https://doi.org/10.4049/jimmunol.178.7.4022. PubMed PMID: 17371955

    Article  CAS  PubMed  Google Scholar 

  89. Davidson TS, Shevach EM. Polyclonal treg cells modulate t effector cell trafficking. Eur J Immunol. 2011;41(10):2862–70. https://doi.org/10.1002/eji.201141503. PubMed PMID: 21728170; PMCID: PMC3813905

    Article  CAS  PubMed  Google Scholar 

  90. Vignali DA, Collison LW, Workman CJ. How regulatory t cells work. Nat Rev Immunol. 2008;8(7):523–32. https://doi.org/10.1038/nri2343. PubMed PMID: 18566595; PMCID: PMC2665249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Shevach EM, Thornton AM. Ttregs, ptregs, and itregs: similarities and differences. Immunol Rev. 2014;259(1):88–102. https://doi.org/10.1111/imr.12160. PubMed PMID: 24712461; PMCID: PMC3982187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Dan Xu & Stephen D. Miller

  2. Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

    Sookyong Koh

Authors
  1. Dan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sookyong Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen D. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dan Xu .

Editor information

Editors and Affiliations

  1. Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA

    Damir Janigro

  2. INSERM, Strasbourg, France

    Astrid Nehlig

  3. Cerebrovascular and Glia Research, Department of Neuroscience, Institute of Functional Genomics (UMR 5203 CNRS – U 1191 INSERM, University of Montpellier), Montpellier, France

    Nicola Marchi

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Xu, D., Koh, S., Miller, S.D. (2021). Role of Regulatory T cells in Epilepsy. In: Janigro, D., Nehlig, A., Marchi, N. (eds) Inflammation and Epilepsy: New Vistas. Progress in Inflammation Research, vol 88. Springer, Cham. https://doi.org/10.1007/978-3-030-67403-8_9

Download citation

Publish with us

Policies and ethics

Search

Navigation