Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft-versus-host Disease

Complement component C3 mediates Th1/Th17 polarization in human T-cell activation and cutaneous GVHD

Bone Marrow Transplantation volume 49, pages 972–976 (2014)Cite this article

Subjects

Abstract

The complement system has been shown to regulate T-cell activation and alloimmune responses in GVHD. Mice deficient in the central component of complement system C3 have significantly lower GVHD-related mortality/morbidity, and C3 modulates Th1/Th17 polarization in mouse GVHD. To investigate whether anticomplement therapy has any impact on human T-cell activation, a drug candidate Compstatin was used to inhibit C3 activation in this study. We found the frequency of IFN-γ (Th1)-, IL-4 (Th2)-, IL-17 (Th17)-, IL-2- and TNF-α-producing cells were significantly reduced among activated CD4+ cells in the presence of Compstatin. Compstatin treatment decreased the proliferation of both CD4+ and CD8+ T cells upon TCR stimulation. However, Compstatin does not affect the production of IL-2 and TNF-α in activated CD8+ T cells, and the differentiation of CD8+ T cells into distinct memory and effector subsets remained intact. Furthermore, we examined complement deposition in skin and lip biopsy samples of patients diagnosed with cutaneous GVHD. C3 deposition was detected in the squamous epithelium and dermis, blood vessels and damaged sweat glands, and was associated with gland damage and regeneration. We conclude that C3 mediates Th1/Th17 polarization in human T-cell activation and skin GVHD in patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Korngold R Friedman TM . Murine models for graft-versus-host disease. In: Blume KG, Forman SJ, Appelbaum FR (eds). Thomas’s Hematopoietic Cell Transplantation, 3rd edn. Blackwell Publishing: Malden, MA, USA, 2004; pp 353–368.

    Google Scholar 

  2. Sale GE Shulman HM Hackman RC . Pathology of hematopoietic cell transplantation. In: Blume KG, Forman SJ, Appelbaum FR (eds). Thomas’s Hematopoietic Cell Transplantation, 3rd edn. Blackwell Publishing Ltd: Malden, MA, USA, 2004; pp 286–299.

    Google Scholar 

  3. Shlomchik WD . Graft-versus-host disease. Nat Rev Immunol 2007; 7: 340–352.

    Article  CAS  Google Scholar 

  4. Ferrara JLM, Cooke KR, Teshima T . The Pathophysiology of graft-vs-host disease. In: Ferrara JLM, Cooke KR, Deeg HJ (eds). Graft-vs-Host-Disease, 3rd edn. Marcel Dekker: New York, NY, USA, 2005; pp 1–34.

    Google Scholar 

  5. Kemper C, Atkinson JP . T-cell regulation: with complements from innate immunity. Nat Rev Immunol 2007; 7: 9–18.

    Article  CAS  Google Scholar 

  6. Heeger PS, Kemper C . Novel roles of complement in T effector cell regulation. Immunobiology 2012; 217: 216–224.

    Article  CAS  Google Scholar 

  7. Pratt JR, Basheer SA, Sacks SH . Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 2002; 8: 582–587.

    Article  CAS  Google Scholar 

  8. Zhou W, Medof ME, Heeger PS, Sacks S . Graft-derived complement as a mediator of transplant injury. Curr Opin Immunol 2007; 19: 569–576.

    Article  CAS  Google Scholar 

  9. Ma Q, Li D, Nurieva R, Patenia R, Bassett R, Cao W et al. Reduced GVHD in C3-deficient mice is associated with the decrease of donor Th1/Th17 differentiation. Biol Blood Marrow Transplant 2012; 18: 1174–1181.

    Article  CAS  Google Scholar 

  10. Kwan WH, Hashimoto D, Paz-Artal E, Ostrow K, Greter M, Raedler H et al. Antigen-presenting cell-derived complement modulates graft-versus-host disease. J Clin Invest 2012; 122: 2234–2238.

    Article  CAS  Google Scholar 

  11. Coghill JM, Sarantopoulos S, Moran TP, Murphy WJ, Blazar BR, Serody JS . Effector CD4 + T cells, the cytokines they generate, and GVHD: something old and something new. Blood 2011; 117: 3268–3276.

    Article  CAS  Google Scholar 

  12. Niculescu F, Niculescu T, Nguyen P, Puliaev R, Papadimitriou JC, Gaspari A et al. Both apoptosis and complement membrane attack complex deposition are major features of murine acute graft-vs-host disease. Exp Mol Pathol 2005; 79: 136–145.

    Article  CAS  Google Scholar 

  13. Tsoi MS, Storb R, Jones E, Weiden PL, Shulman H, Witherspoon R et al. Deposition of IgM and complement at the dermoepidermal junction in acute and chronic cutaneous graft-vs-host disease in man. J Immunol 1978; 120: 1485–1492.

    CAS  PubMed  Google Scholar 

  14. Martires KJ, Baird K, Steinberg SM, Grkovic L, Joe GO, Williams KM et al. Sclerotic-type chronic GVHD of the skin: clinical risk factors, laboratory markers, and burden of disease. Blood 2011; 118: 4250–4257.

    Article  CAS  Google Scholar 

  15. Morikis D, Assa-Munt N, Sahu A, Lambris JD . Solution structure of Compstatin, a potent complement inhibitor. Protein Sci 1998; 7: 619–627.

    Article  CAS  Google Scholar 

  16. Nilsson B, Larsson R, Hong J, Elgue G, Ekdahl KN, Sahu A et al. Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation. Blood 1998; 92: 1661–1667.

    CAS  PubMed  Google Scholar 

  17. Li D, Li Y, Hernandez JA, Patenia R, Kim TK, Khalili J et al. Lovastatin inhibits T-cell proliferation while preserving the cytolytic function of EBV, CMV, and MART-1-specific CTLs. J Immunother 2010; 33: 975–982.

    Article  CAS  Google Scholar 

  18. Palmer LA, Sale GE, Balogun JI, Li D, Jones D, Molldrem JJ et al. Chemokine receptor CCR5 mediates alloimmune responses in graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16: 311–319.

    Article  CAS  Google Scholar 

  19. Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 1997; 186: 1407–1418.

    Article  CAS  Google Scholar 

  20. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A . Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999; 401: 708–712.

    Article  CAS  Google Scholar 

  21. Tussey L, Speller S, Gallimore A, Vessey R . Functionally distinct CD8 + memory T cell subsets in persistent EBV infection are differentiated by migratory receptor expression. Eur J Immunol 2000; 30: 1823–1829.

    Article  CAS  Google Scholar 

  22. Purwar R, Bäumer W, Niebuhr M, Tschernig T, Kietzmann M, Werfel T . A protective role of complement component 3 in T cell-mediated skin inflammation. Exp Dermatol 2011; 20: 709–714.

    Article  CAS  Google Scholar 

  23. Socié G, Blazar BR . Acute graft-versus-host disease: from the bench to the bedside. Blood 2009; 114: 4327–4336.

    Article  Google Scholar 

  24. Anderson BE, McNiff J, Yan J, Doyle H, Mamula M, Shlomchik MJ et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest 2003; 112: 101–108.

    Article  CAS  Google Scholar 

  25. Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ . Transfer of allogeneic CD62L− memory T cells without graft-versus-host disease. Blood 2004; 103: 1534–1541.

    Article  CAS  Google Scholar 

  26. Zhang Y, Joe G, Zhu J, Carroll R, Levine B, Hexner E et al. Dendritic cell-activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity. Blood 2004; 103: 3970–3978.

    Article  CAS  Google Scholar 

  27. Reis ES, Barbuto JA, Kohl J, Isaac L . Impaired dendritic cell differentiation and maturation in the absence of C3. Mol Immunol 2008; 45: 1952–1962.

    Article  CAS  Google Scholar 

  28. Kerekes K, Cooper PD, Prechl J, Józsi M, Bajtay Z, Erdei A . Adjuvant effect of gamma-inulin is mediated by C3 fragments deposited on antigen-presenting cells. J Leukoc Biol 2001; 69: 69–74.

    CAS  PubMed  Google Scholar 

  29. Peng Q, Li K, Patel H, Sacks SH, Zhou W . Dendritic cell synthesis of C3 is required for full T cell activation and development of a Th1 phenotype. J Immunol 2006; 176: 3330–3341.

    Article  CAS  Google Scholar 

  30. Woodruff TM, Nandakumar KS, Tedesco F . Inhibiting the C5-C5a receptor axis. Mol Immunol 2001; 48: 1631–1642.

    Article  Google Scholar 

Download references

Acknowledgements

The work was supported in part by ACS grant RSG-08-183-01-LIB (QM), NIH/NIAID grant 1R21AI101932 (QM and VA-K) and CPRIT grant RP101374 (VA-K). DL, RC, RP and MX-S performed the research. DL, RC, KYT and GES analyzed the data. AMA, REC and VA-K participated in discussions and wrote the paper. QM designed the research, analyzed the data and wrote the paper.

Author information

Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA,

    Q Ma, D Li, R Carreño, R Patenia, M Xydes-Smith, A M Alousi & R E Champlin

  2. Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX, USA,

    K Y Tsai

  3. Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA,

    K Y Tsai

  4. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,

    G E Sale

  5. Department of Benign Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, USA,

    V Afshar-Kharghan

Authors
  1. Q Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Carreño
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Patenia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Y Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Xydes-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A M Alousi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R E Champlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G E Sale
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. V Afshar-Kharghan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Q Ma.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, Q., Li, D., Carreño, R. et al. Complement component C3 mediates Th1/Th17 polarization in human T-cell activation and cutaneous GVHD. Bone Marrow Transplant 49, 972–976 (2014). https://doi.org/10.1038/bmt.2014.75

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2014.75

This article is cited by

Search

Advanced search

Quick links