Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Enforced Expression of CXCR5 Drives T Follicular Regulatory-Like Features in Foxp3+ T Cells

  • Kim, Young Uk (Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, The University of Texas Medical School) ;
  • Kim, Byung-Seok (Laboratory of Immune Regulation, Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University) ;
  • Lim, Hoyong (Laboratory of Immune Regulation, Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University) ;
  • Wetsel, Rick A. (Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, The University of Texas Medical School) ;
  • Chung, Yeonseok (Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, The University of Texas Medical School)
  • Received : 2016.04.05
  • Accepted : 2016.06.07
  • Published : 2017.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

$CXCR5^+$ T follicular helper (Tfh) cells are associated with aberrant autoantibody production in patients with antibody-mediated autoimmune diseases including lupus. Follicular regulatory T (Tfr) cells expressing CXCR5 and Bcl6 have been recently identified as a specialized subset of $Foxp3^+$ regulatory T (Treg) cells that control germinal center reactions. In this study, we show that retroviral transduction of CXCR5 gene in $Foxp3^+$ Treg cells induced a stable expression of functional CXCR5 on their surface. The Cxcr5-transduced Treg cells maintained the expression of Treg cell signature genes and the suppressive activity. The expression of CXCR5 as well as Foxp3 in the transduced Treg cells appeared to be stable in vivo in an adoptive transfer experiment. Moreover, Cxcr5-transduced Treg cells preferentially migrated toward the CXCL13 gradient, leading to an effective suppression of antibody production from B cells stimulated with Tfh cells. Therefore, our results demonstrate that enforced expression of CXCR5 onto Treg cells efficiently induces Tfr cell-like properties, which might be a promising cellular therapeutic approach for the treatment of antibody-mediated autoimmune diseases.

Keywords

References

  1. Ansel, K. M., McHeyzer-Williams, L. J., Ngo, V. N., McHeyzer-Williams, M. G. and Cyster, J. G. (1999) In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190, 1123-1134. https://doi.org/10.1084/jem.190.8.1123
  2. Bailey-Bucktrout, S. L., Martinez-Llordella, M., Zhou, X., Anthony, B., Rosenthal, W., Luche, H., Fehling, H. J. and Bluestone, J. A. (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39, 949-962. https://doi.org/10.1016/j.immuni.2013.10.016
  3. Batten, M., Ramamoorthi, N., Kljavin, N. M., Ma, C. S., Cox, J. H., Dengler, H. S., Danilenko, D. M., Caplazi, P., Wong, M., Fulcher, D. A., Cook, M. C., King, C., Tangye, S. G., de Sauvage, F. J. and Ghilardi, N. (2010) IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells. J. Exp. Med. 207, 2895-2906. https://doi.org/10.1084/jem.20100064
  4. Blat, D., Zigmond, E., Alteber, Z., Waks, T. and Eshhar, Z. (2014) Suppression of murine colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells. Mol. Ther. 22, 1018-1028. https://doi.org/10.1038/mt.2014.41
  5. Campbell, D. J. and Koch, M. A. (2011) Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat. Rev. Immunol. 11, 119-130. https://doi.org/10.1038/nri2916
  6. Chang, J.-H. and Chung, Y. (2014) Regulatory T cells in B cell follicles. Immune Netw. 14, 227-236. https://doi.org/10.4110/in.2014.14.5.227
  7. Charbonnier, L. M., Janssen, E., Chou, J., Ohsumi, T. K., Keles, S., Hsu, J. T., Massaad, M. J., Garcia-Lloret, M., Hanna-Wakim, R., Dbaibo, G., Alangari, A. A., Alsultan, A., Al-Zahrani, D., Geha, R. S. and Chatila, T. A. (2015) Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J. Allergy Clin. Immunol. 135, 217-227. https://doi.org/10.1016/j.jaci.2014.10.019
  8. Chung, Y., Tanaka, S., Chu, F., Nurieva, R. I., Martinez, G. J., Rawal, S., Wang, Y. H., Lim, H., Reynolds, J. M., Zhou, X. H., Fan, H. M., Liu, Z. M., Neelapu, S. S. and Dong, C. (2011) Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983-988. https://doi.org/10.1038/nm.2426
  9. Crotty, S. (2011) Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621-663. https://doi.org/10.1146/annurev-immunol-031210-101400
  10. Crotty, S. (2014) T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529-542. https://doi.org/10.1016/j.immuni.2014.10.004
  11. Ding, Y., Li, J., Yang, P., Luo, B., Wu, Q., Zajac, A. J., Wildner, O., Hsu, H. C. and Mountz, J. D. (2014) Interleukin-21 promotes germinal center reaction by skewing the follicular regulatory T cell to follicular helper T cell balance in autoimmune BXD2 mice. Arthritis Rheumatol. 66, 2601-2612. https://doi.org/10.1002/art.38735
  12. Eddahri, F., Denanglaire, S., Bureau, F., Spolski, R., Leonard, W. J., Leo, O. and Andris, F. (2009) Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. Blood 113, 2426-2433. https://doi.org/10.1182/blood-2008-04-154682
  13. Elinav, E., Adam, N., Waks, T. and Eshhar, Z. (2009) Amelioration of colitis by genetically engineered murine regulatory T cells redirected by antigen-specific chimeric receptor. Gastroenterology 136, 1721-1731. https://doi.org/10.1053/j.gastro.2009.01.049
  14. Geldres, C., Savoldo, B. and Dotti, G. (2016) Chimeric antigen receptor-redirected T cells return to the bench. Semin. Immunol. 28, 3-9. https://doi.org/10.1016/j.smim.2015.12.001
  15. Gunn, M. D., Ngo, V. N., Ansel, K. M., Ekland, E. H., Cyster, J. G. and Williams, L. T. (1998) A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature 391, 799-803. https://doi.org/10.1038/35876
  16. Guo, Y., Wang, Y. and Han, W. (2016) Chimeric Antigen Receptor-Modified T Cells for Solid Tumors: Challenges and Prospects. J. Immunol. Res. 016, 3850839.
  17. Hardtke, S., Ohl, L. and Forster, R. (2005) Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood 106, 1924-1931. https://doi.org/10.1182/blood-2004-11-4494
  18. Haynes, N. M., Allen, C. D., Lesley, R., Ansel, K. M., Killeen, N. and Cyster, J. G. (2007) Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J. Immunol. 179, 5099-5108. https://doi.org/10.4049/jimmunol.179.8.5099
  19. Johnston, R. J., Choi, Y. S., Diamond, J. A., Yang, J. A. and Crotty, S. (2012) STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209, 243-250. https://doi.org/10.1084/jem.20111174
  20. Johnston, R. J., Poholek, A. C., DiToro, D., Yusuf, I., Eto, D., Barnett, B., Dent, A. L., Craft, J. and Crotty, S. (2009) Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006-1010. https://doi.org/10.1126/science.1175870
  21. Kim, Y. U., Lim, H., Jung, H. E., Wetsel, R. A. and Chung, Y. (2015) Regulation of autoimmune germinal center reactions in lupus-prone BXD2 mice by follicular helper T cells. PLoS ONE 10, e0120294. https://doi.org/10.1371/journal.pone.0120294
  22. Komatsu, N., Okamoto, K., Sawa, S., Nakashima, T., Oh-hora, M., Kodama, T., Tanaka, S., Bluestone, J. A. and Takayanagi, H. (2014) Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62-68. https://doi.org/10.1038/nm.3432
  23. Legler, D. F., Loetscher, M., Roos, R. S., Clark-Lewis, I., Baggiolini, M. and Moser, B. (1998) B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J. Exp. Med. 187, 655-660. https://doi.org/10.1084/jem.187.4.655
  24. Linterman, M. A., Pierson, W., Lee, S. K., Kallies, A., Kawamoto, S., Rayner, T. F., Srivastava, M., Divekar, D. P., Beaton, L., Hogan, J. J., Fagarasan, S., Liston, A., Smith, K. G. and Vinuesa, C. G. (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975-982. https://doi.org/10.1038/nm.2425
  25. Liu, X., Chen, X., Zhong, B., Wang, A., Wang, X., Chu, F., Nurieva, R. I., Yan, X., Chen, P., van der Flier, L. G., Nakatsukasa, H., Neelapu, S. S., Chen, W., Clevers, H., Tian, Q., Qi, H., Wei, L. and Dong, C. (2014) Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature 507, 513-518. https://doi.org/10.1038/nature12910
  26. Lutz, M. B. (2016) Induction of $CD4^{+}$ regulatory and polarized effector/helper T cells by dendritic cells. Immune Netw. 16, 13-25. https://doi.org/10.4110/in.2016.16.1.13
  27. MacDonald, K. G., Hoeppli, R. E., Huang, Q., Gillies, J., Luciani, D. S., Orban, P. C., Broady, R. and Levings, M. K. (2016) Alloantigenspecific regulatory T cells generated with a chimeric antigen receptor. J. Clin. Invest. 126, 1413-1424. https://doi.org/10.1172/JCI82771
  28. Miyao, T., Floess, S., Setoguchi, R., Luche, H., Fehling, H. J., Waldmann, H., Huehn, J. and Hori, S. (2012) Plasticity of $Foxp^{3+}$ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36, 262-275. https://doi.org/10.1016/j.immuni.2011.12.012
  29. Muller, G. and Lipp, M. (2001) Signal transduction by the chemokine receptor CXCR5: structural requirements for G protein activation analyzed by chimeric CXCR1/CXCR5 molecules. Biol. Chem. 382, 1387-1397.
  30. Nurieva, R. I., Chung, Y., Hwang, D., Yang, X. O., Kang, H. S., Ma, L., Wang, Y. H., Watowich, S. S., Jetten, A. M., Tian, Q. and Dong, C. (2008) Generation of T follicular helper cells is mediated by interleukin- 21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138-149. https://doi.org/10.1016/j.immuni.2008.05.009
  31. Nurieva, R. I., Chung, Y., Martinez, G. J., Yang, X. O., Tanaka, S., Matskevitch, T. D., Wang, Y. H. and Dong, C. (2009) Bcl6 mediates the development of T follicular helper cells. Science 325, 1001-1005. https://doi.org/10.1126/science.1176676
  32. Nurieva, R. I., Podd, A., Chen, Y., Alekseev, A. M., Yu, M., Qi, X., Huang, H., Wen, R., Wang, J., Li, H. S., Watowich, S. S., Qi, H., Dong, C. and Wang, D. (2012) STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 287, 11234-11239. https://doi.org/10.1074/jbc.M111.324046
  33. Riley, J. L., June, C. H. and Blazar, B. R. (2009) Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity 30, 656-665. https://doi.org/10.1016/j.immuni.2009.04.006
  34. Rubtsov, Y. P., Niec, R. E., Josefowicz, S., Li, L., Darce, J., Mathis, D., Benoist, C. and Rudensky, A. Y. (2010) Stability of the regulatory T cell lineage in vivo. Science 329, 1667-1671. https://doi.org/10.1126/science.1191996
  35. Sage, P. T., Francisco, L. M., Carman, C. V. and Sharpe, A. H. (2013) The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat. Immunol. 14, 152-161. https://doi.org/10.1038/ni.2496
  36. Sage, P. T., Paterson, A. M., Lovitch, S. B. and Sharpe, A. H. (2014) The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 41, 1026-1039. https://doi.org/10.1016/j.immuni.2014.12.005
  37. Sage, P. T. and Sharpe, A. H. (2015) T follicular regulatory cells in the regulation of B cell responses. Trends Immunol. 36, 410-418. https://doi.org/10.1016/j.it.2015.05.005
  38. Sakaguchi, S., Vignali, D. A., Rudensky, A. Y., Niec, R. E. and Waldmann, H. (2013) The plasticity and stability of regulatory T cells. Nat. Rev. Immunol. 13, 461-467. https://doi.org/10.1038/nri3464
  39. Sakaguchi, S., Yamaguchi, T., Nomura, T. and Ono, M. (2008) Regulatory T cells and immune tolerance. Cell 133, 775-787. https://doi.org/10.1016/j.cell.2008.05.009
  40. Suurmond, J. and Diamond, B. (2015) Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity. J. Clin. Invest. 125, 2194-2202. https://doi.org/10.1172/JCI78084
  41. Trzonkowski, P., Bacchetta, R., Battaglia, M., Berglund, D., Bohnenkamp, H. R., ten Brinke, A., Bushell, A., Cools, N., Geissler, E. K., Gregori, S., Marieke van Ham, S., Hilkens, C., Hutchinson, J. A., Lombardi, G., Madrigal, J. A., Marek-Trzonkowska, N., Martinez-Caceres, E. M., Roncarolo, M. G., Sanchez-Ramon, S., Saudemont, A. and Sawitzki, B. (2015) Hurdles in therapy with regulatory T cells. Sci. Transl. Med. 7, 304ps18. https://doi.org/10.1126/scitranslmed.aaa7721
  42. Ueno, H., Banchereau, J. and Vinuesa, C. G. (2015) Pathophysiology of T follicular helper cells in humans and mice. Nat. Immunol. 16, 142-152. https://doi.org/10.1038/ni.3054
  43. Vinuesa, C. G., Linterman, M. A., Yu, D. and MacLennan, I. C. (2016) Follicular helper T cells. Annu. Rev. Immunol. 34, 335-368. https://doi.org/10.1146/annurev-immunol-041015-055605
  44. Wahren-Herlenius, M. and Dorner, T. (2013) Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 382, 819-831. https://doi.org/10.1016/S0140-6736(13)60954-X
  45. Wang, C. J., Heuts, F., Ovcinnikovs, V., Wardzinski, L., Bowers, C., Schmidt, E. M., Kogimtzis, A., Kenefeck, R., Sansom, D. M. and Walker, L. S. (2015) CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. Proc. Natl. Acad. Sci. U.S.A. 112, 524-529. https://doi.org/10.1073/pnas.1414576112
  46. Wing, J. B., Ise, W., Kurosaki, T. and Sakaguchi, S. (2014) Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. Immunity 41, 1013-1025. https://doi.org/10.1016/j.immuni.2014.12.006
  47. Wollenberg, I., Agua-Doce, A., Hernandez, A., Almeida, C., Oliveira, V. G., Faro, J. and Graca, L. (2011) Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J. Immunol. 187, 4553-4560. https://doi.org/10.4049/jimmunol.1101328
  48. Yu, D., Rao, S., Tsai, L. M., Lee, S. K., He, Y., Sutcliffe, E. L., Srivastava, M., Linterman, M., Zheng, L., Simpson, N., Ellyard, J. I., Parish, I. A., Ma, C. S., Li, Q. J., Parish, C. R., Mackay, C. R. and Vinuesa, C. G. (2009) The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457-468. https://doi.org/10.1016/j.immuni.2009.07.002
  49. Zhou, X., Bailey-Bucktrout, S. L., Jeker, L. T., Penaranda, C., Martinez-Llordella, M., Ashby, M., Nakayama, M., Rosenthal, W. and Bluestone, J. A. (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000-1007. https://doi.org/10.1038/ni.1774

Cited by

  1. Taking regulatory T-cell therapy one step further pp.1087-2418, 2018, https://doi.org/10.1097/MOT.0000000000000566
  2. Control and prevention of kidney transplant rejection: the role and possibilities for the clinical use of regulatory T-cells in transplantation vol.2019, pp.9, 2019, https://doi.org/10.17116/hirurgia201909180
  3. Regulatory Effect of Sishen Pill on Tfh Cells in Mice With Experimental Colitis vol.11, pp.None, 2017, https://doi.org/10.3389/fphys.2020.00589
  4. Technical Considerations in Ex Vivo Human Regulatory T Cell Migration and Suppression Assays vol.9, pp.2, 2017, https://doi.org/10.3390/cells9020487
  5. Follicular Regulatory T Cells in Systemic Lupus Erythematosus vol.2021, pp.None, 2017, https://doi.org/10.1155/2021/9943743
  6. Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation vol.11, pp.None, 2017, https://doi.org/10.3389/fimmu.2020.612848
  7. Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges vol.22, pp.18, 2017, https://doi.org/10.3390/ijms22189676