Skip to main content
SpringerLink
Log in

Change of paradigm: CD8+ T cells as important helper for CD4+ T cells during asthma and autoimmune encephalomyelitis

  • Review
  • Published:
Allergo Journal International Aims and scope Submit manuscript

Summary

The activation of naive CD4+ and CD8+ T cells in response to antigen and their subsequent proliferation and differentiation into effectors are important features of a cell-mediated immune response. CD4+ T cells (also known as T helper cells, Th) differentiate into several subpopulations including Th1, Th2, Th9, Th17, Tfh and Treg cells, characterized by specific cytokine profiles and effector functions. However, recent evidence indicates that CD8+ T cells (termed cytotoxic T lymphocytes, CTLs or Tc cells) can differentiate into subpopulations with similar characteristics denoted as Tc2, Tc9, Tc17 and CD8+ Treg cells in addition to CTLs. Although these subpopulations accomplish important protective functions, their uncontrolled responses cause immunopathology including allergy and autoimmunity. Our recent findings indicate a change of paradigm: during these pathologic responses, CD8+ T cell subpopulations act as strong helpers for the activity of CD4+ T cells rather than being cytotoxic. In this review, we focus on the role of Th2, Th9, Th17 as well as Tc9 and Tc17 cells in asthma and autoimmune encephalomyelitis and on their interaction during these immunopathologic responses.

Cite this as Huber M, Lohoff M. Change of paradigm: CD8+ T cells as important helper for CD4+ T cells during asthma and autoimmune encephalomyelitis. Allergo J Int 2015;24:8–15 DOI: 10.1007/s40629-015-0038-4

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

AD:

Atopic dermatitis

AHR:

Airway hyperresponsiveness

EAE:

Experimental autoimmune encephalomyelitis

APC:

Antigen-presenting cells

CCR6:

Chemokine receptor 6

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CTL:

Cytotoxic T lymphocyte, CD8+ T cell

IgE:

Immunoglobulin E

IL:

Interleukin

MHC:

Major histocompatibility complex

MOG:

Myelin oligodendrocyte protein

MS:

Multiple sclerosis

Tc:

Cytotoxic T lymphocyte

TGF-β:

Transforming growth factor-β

Th:

T helper lymphocyte, CD4+ cell

References

  1. Zhu J and Paul WE. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 2010;238:247–262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Kaech SM and Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 2012;12:749–761

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Mittrucker HW, Visekruna A and Huber M. Heterogeneity in the Differentiation and Function of CD8 T Cells. Arch Immunol Ther Exp (Warsz) 2014

    Google Scholar 

  4. Schmitt E, Klein M and Bopp T. Th9 cells, new players in adaptive immunity. Trends Immunol 2014;35:61–68

    Article  CAS  PubMed  Google Scholar 

  5. Gaffen SL, Jain R, Garg AV and Cua DJ. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 2014;14:585–600

    Article  CAS  PubMed  Google Scholar 

  6. Zhu J, Yamane H and Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 2010;28:445–489

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Kim HY, DeKruyff RH and Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol 2010;11:577–584

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Shalaby KH and Martin JG. Overview of asthma; the place of the T cell. Curr Opin Pharmacol 2010;10:218–225

    Article  CAS  PubMed  Google Scholar 

  9. Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 2010;33:192–202

    Article  CAS  PubMed  Google Scholar 

  10. Chang HC, Sehra S, Goswami R, Yao W, Yu Q, Stritesky GL, et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol 2010;11:527–534

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Jabeen R, Goswami R, Awe O, Kulkarni A, Nguyen E T, Attenasio, A., et al. Th9 cell development requires a BATFregulated transcriptional network. J Clin Invest 2013;123:4641–4653

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Jones C P, Gregory LG, Causton B, Campbell GA and Lloyd CM. Activin A and TGF-beta promote T(H)9 cell-mediated pulmonary allergic pathology. J Allergy Clin Immunol 2012;129:1000–1010 e1003

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Erpenbeck VJ, Hohlfeld JM, Volkmann B, Hagenberg A, Geldmacher H, Braun A, et al. Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J Allergy Clin Immunol 2003;111: 1319–1327

    Article  CAS  PubMed  Google Scholar 

  14. Shimbara A, Christodoulopoulos P, Soussi-Gounni A, Olivenstein R, Nakamura Y, Levitt RC, et al. J. IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma. J Allergy Clin Immunol 2000;105:108–115

    Article  CAS  PubMed  Google Scholar 

  15. Fugger L, Friese MA and Bell JI. From genes to function: the next challenge to understanding multiple sclerosis. Nat Rev Immunol 2009;9:408–417

    Article  CAS  PubMed  Google Scholar 

  16. Hafler DA. Multiple sclerosis. J Clin Invest 2004;113:788–794

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Goverman J. Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 2009;9:393–407

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000;13:715–725

    Article  CAS  PubMed  Google Scholar 

  19. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003;421:744–748

    Article  CAS  PubMed  Google Scholar 

  20. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. A. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005;201:233–240

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006;126:1121–1133

    Article  CAS  PubMed  Google Scholar 

  22. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 2008;28:29–39

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, et al. RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 2011;12:560–567

    Article  CAS  PubMed  Google Scholar 

  24. Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P, et al. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 2007;8:958–966

    Article  PubMed  Google Scholar 

  25. Luchtman DW, Ellwardt E, Larochelle C and Zipp F. IL-17 and related cytokines involved in the pathology and immunotherapy of multiple sclerosis: Current and future developments. Cytokine Growth Factor Rev 2014;25:403–413

    Article  CAS  PubMed  Google Scholar 

  26. Chang SY, Song JH, Guleng B, Cotoner CA, Arihiro S, Zhao Y, et al. Circulatory antigen processing by mucosal dendritic cells controls CD8(+) T cell activation. Immunity 2013;38:153–165

    Article  CAS  PubMed  Google Scholar 

  27. Visekruna A, Ritter J, Scholz T, Campos L, Guralnik A, Poncette L, et al. Tc9 cells, a new subset of CD8(+) T cells, support Th2-mediated airway inflammation. Eur J Immunol 2013;43:606–618

    Article  CAS  PubMed  Google Scholar 

  28. Lu Y, Hong B, Li H, Zheng Y, Zhang M, Wang S, et al. Tumor-specific IL-9-producing CD8+ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers. Proc Natl Acad Sci U S A 2014;111:2265–2270

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Hamzaoui A, Chaouch N, Grairi H, Ammar J and Hamzaoui K. Inflammatory process of CD8+ CD28- T cells in induced sputum from asthmatic patients. Mediators Inflamm 2005;2005:160–166

    Article  PubMed Central  PubMed  Google Scholar 

  30. van Rensen EL, Sont JK, Evertse CE, Willems LN, Mauad T, Hiemstra PS, et al. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am J Respir Crit Care Med 2005;172:837–841

    Article  PubMed  Google Scholar 

  31. Miyahara N, Swanson BJ, Takeda K, Taube C, Miyahara S, Kodama T, et al. Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nat Med 2004;10:865–869

    Article  CAS  PubMed  Google Scholar 

  32. Koya T, Miyahara N, Takeda K, Matsubara S, Matsuda H, Swasey C, et al. CD8+ T cell-mediated airway hyperresponsiveness and inflammation is dependent on CD4+IL-4+ T cells. J Immunol 2007;179:2787–2796

    Article  CAS  PubMed  Google Scholar 

  33. Wells JW, Cowled CJ, Giorgini A, Kemeny DM and Noble A. Regulation of allergic airway inflammation by class Irestricted allergen presentation and CD8 T-cell infiltration. J Allergy Clin Immunol 2007;119:226–234

    Article  CAS  PubMed  Google Scholar 

  34. Enomoto N, Hyde E, Ma JZ, Yang J, Forbes-Blom E, Delahunt B, et al. Allergen-specific CTL require perforin expression to suppress allergic airway inflammation. J Immunol 2012;188:1734–1741

    Article  CAS  PubMed  Google Scholar 

  35. Tang Y, Guan SP, Chua BY, Zhou Q, Ho AW, Wong KH et al. Antigen-specific effector CD8 T cells regulate allergic responses via IFN-gamma and dendritic cell function. J Allergy Clin Immunol 2012;129:1611–1620 e1614

    Article  CAS  PubMed  Google Scholar 

  36. Wilhelm C, Hirota K, Stieglitz B, Van Snick J, Tolaini M, Lahl K, et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol 2011;12:1071–1077

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Tan C, Aziz MK, Lovaas JD, Vistica BP, Shi G, Wawrousek EF et al. Antigen-specific Th9 cells exhibit uniqueness in their kinetics of cytokine production and short retention at the inflammatory site. J Immunol 2010;185:6795–6801

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Boguniewicz M and Leung DY. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 2011;242:233–246

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T, et al. IL-22-producing „T22“ T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol 2009;123:1244–1252 e1242

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Yao W, Tepper RS and Kaplan MH. Predisposition to the development of IL-9-secreting T cells in atopic infants. J Allergy Clin Immunol 2011;128:1357–1360 e1355

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Ford ML and Evavold BD. Specificity, magnitude, and kinetics of MOG-specific CD8+ T cell responses during experimental autoimmune encephalomyelitis. Eur J Immunol 2005;35:76–85

    Article  CAS  PubMed  Google Scholar 

  42. Huber M, Heink S, Grothe H, Guralnik A, Reinhard K, Elflein K, et al. A Th17-like developmental process leads to CD8(+) Tc17 cells with reduced cytotoxic activity. Eur J Immunol 2009;39:1716–1725

    Article  CAS  PubMed  Google Scholar 

  43. Hamada H, Garcia-Hernandez Mde L, Reome JB, Misra SK, Strutt TM, McKinstry KK, et al. L. Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. J Immunol 2009;182:3469–3481

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Yen HR, Harris TJ, Wada S, Grosso JF, Getnet D, Goldberg MV, et al. Tc17 CD8 T cells: functional plasticity and subset diversity. J Immunol 2009;183:7161–7168

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Tzartos JS, Friese M A, Craner M J, Palace J, Newcombe J, Esiri MM et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 2008;172:146–155

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Huber M, Heink S, Pagenstecher A, Reinhard K, Ritter J, Visekruna A, et al. IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis. J Clin Invest 2013;123:247–260

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 2009;10:514–523

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg, Germany

    Magdalena Huber & Michael Lohoff

  2. Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Hans-Meerwein-Straße 2, 35032, Marburg, Germany

    Magdalena Huber

Authors
  1. Magdalena Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Lohoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Magdalena Huber.

Additional information

Conflict of interest

The authors states that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huber, M., Lohoff, M. Change of paradigm: CD8+ T cells as important helper for CD4+ T cells during asthma and autoimmune encephalomyelitis. Allergo J Int 24, 8–15 (2015). https://doi.org/10.1007/s40629-015-0038-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40629-015-0038-4

Key words

Search

Navigation