Molecules and Cells

  • 제39권6호
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  • Pages.468-476
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  • 2016
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
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PLZF+ Innate T Cells Support the TGF-β-Dependent Generation of Activated/Memory-Like Regulatory T Cells

  • Kang, Byung Hyun (Postgraduate Course of Translational Medicine, Seoul National University College of Medicine) ;
  • Park, Hyo Jin (Department of Pathology, Seoul National University College of Medicine) ;
  • Park, Hi Jung (Postgraduate Course of Translational Medicine, Seoul National University College of Medicine) ;
  • Lee, Jae-Il (Postgraduate Course of Translational Medicine, Seoul National University College of Medicine) ;
  • Park, Seong Hoe (Postgraduate Course of Translational Medicine, Seoul National University College of Medicine) ;
  • Jung, Kyeong Cheon (Postgraduate Course of Translational Medicine, Seoul National University College of Medicine)
  • 투고 : 2016.01.06
  • 심사 : 2016.03.31
  • 발행 : 2016.06.30
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초록

PLZF-expressing invariant natural killer T cells and CD4 T cells are unique subsets of innate T cells. Both are selected via thymocyte-thymocyte interaction, and they contribute to the generation of activated/memory-like CD4 and CD8 T cells in the thymus via the production of IL-4. Here, we investigated whether $PLZF^+$ innate T cells also affect the development and function of $Foxp3^+$ regulatory CD4 T cells. Flow cytometry analysis of the thymus and spleen from both CIITA transgenic C57BL/6 and wild-type BALB/c mice, which have abundant $PLZF^+$ CD4 T cells and invariant natural killer T cells, respectively, revealed that $Foxp3^+$ T cells in these mice exhibited a $CD103^+$ activated/memorylike phenotype. The frequency of $CD103^+$ regulatory T cells was considerably decreased in $PLZF^+$ cell-deficient $CIITA^{Tg}Plzf^{lu/lu}$ and $BALB/c.CD1d^{-/-}$ mice as well as in an IL-4-deficient background, such as in $CIITA^{Tg}IL-4^{-/-}$ and $BALB/c.IL-4^{-/-}$ mice, indicating that the acquisition of an activated/ memory-like phenotype was dependent on $PLZF^+$ innate T cells and IL-4. Using fetal thymic organ culture, we further demonstrated that IL-4 in concert with TGF-${\beta}$ enhanced the acquisition of the activated/memory-like phenotype of regulatory T cells. In functional aspects, the activated/ memory-like phenotype of Treg cells was directly related to their suppressive function; regulatory T cells of $CIITA^{Tg}PIV^{-/-}$ mice more efficiently suppressed ovalbumin-induced allergic airway inflammation compared with their counterparts from wild-type mice. All of these findings suggest that $PLZF^+$ innate T cells also augmented the generation of activated/memory-like regulation via IL-4 production.

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참고문헌

  1. Alonzo, E.S., and Sant' Angelo, D.B. (2011). Development of PLZF-expressing innate T cells. Curr. Opin. Immunol. 23, 220-227. https://doi.org/10.1016/j.coi.2010.12.016
  2. Annacker, O., Coombes, J.L., Malmstrom, V., Uhlig, H.H., Bourne, T., Johansson-Lindbom, B., Agace, W.W., Parker, C.M., and Powrie, F. (2005). Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J. Exp. Med. 202, 1051-1061. https://doi.org/10.1084/jem.20040662
  3. Banz, A., Peixoto, A., Pontoux, C., Cordier, C., Rocha, B., and Papiernik, M. (2003). A unique subpopulation of $CD4^+$ regulatory T cells controls wasting disease, IL-10 secretion and T cell homeostasis. Eur. J. Immunol. 33, 2419-2428. https://doi.org/10.1002/eji.200324205
  4. Bayer, A.L., Yu, A.X., and Malek, T.R. (2007). Function of the IL-2R for thymic and peripheral $CD4^+CD25^+$ $Foxp3^+$ T regulatory cells. J. Immunol. 178, 4062-4071. https://doi.org/10.4049/jimmunol.178.7.4062
  5. Bird, L. (2010). Regulatory T cells nurtured by TGF${\beta}$. Nat. Rev. Immunol. 10, 466-466.
  6. Burchill, M.A., Yang, J.Y., Vogtenhuber, C., Blazar, B.R., and Farrar, M.A. (2007). IL-2 receptor ${\beta}$-dependent STAT5 activation is required for the development of $Foxp3^+$ regulatory T cells. J. Immunol. 178, 280-290. https://doi.org/10.4049/jimmunol.178.1.280
  7. Chang, L.Y., Lin, Y.C., Kang, C.W., Hsu, C.Y., Chu, Y.Y., Huang, C.T., Day, Y.J., Chen, T.C., Yeh, C.T., and Lin, C.Y. (2012). The indispensable role of CCR5 for in vivo suppressor function of tumor-derived $CD103^+$ effector/memory regulatory T cells. J. Immunol. 189, 567-574. https://doi.org/10.4049/jimmunol.1200266
  8. Choi, E.Y., Park, W.S., Jung, K.C., Chung, D.H., Bae, Y.M., Kim, T.J., Song, H.G., Kim, S.H., Ham, D.I., and Hahn, J.H. et al. (1997). Thymocytes positively select thymocytes in human system. Hum. Immunol. 54, 15-20. https://doi.org/10.1016/S0198-8859(97)00012-8
  9. Choi, E.Y., Jung, K.C., Park, H.J., Chung, D.H., Song, J.S., Yang, S.D., Simpson, E., and Park, S.H. (2005). Thymocyte-thymocyte interaction for efficient positive selection and maturation of CD4 T cells. Immunity 23, 387-396. https://doi.org/10.1016/j.immuni.2005.09.005
  10. Collison, L.W., and Vignali, D.A. (2011). In vitro Treg suppression assays. Methods Mol. Biol. 707, 21-37. https://doi.org/10.1007/978-1-61737-979-6_2
  11. Dardalhon, V., Awasthi, A., Kwon, H., Galileos, G., Gao, W., Sobel, R.A., Mitsdoerffer, M., Strom, T.B., Elyaman, W., and Ho, I.C., et al. (2008). IL-4 inhibits TGF-${\beta}$-induced $Foxp3^+$ T cells and, together with TGF-${\beta}$, generates IL-$9^+$ IL-$10^+$ $Foxp3^-$ effector T cells. Nat. Immunol. 9, 1347-1355. https://doi.org/10.1038/ni.1677
  12. El-Asady, R., Yuan, R., Liu, K., Wang, D., Gress, R.E., Lucas, P.J., Drachenberg, C.B., and Hadley, G.A. (2005). TGF-${\beta}$-dependent CD103 expression by $CD8^+$ T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease. J. Exp. Med. 201, 1647-1657. https://doi.org/10.1084/jem.20041044
  13. Faustino, L., da Fonseca, D.M., Takenaka, M.C., Mirotti, L., Florsheim, E.B., Guereschi, M.G., Silva, J.S., Basso, A.S., and Russo, M. (2013). Regulatory T cells migrate to airways via CCR4 and attenuate the severity of airway allergic inflammation. J. Immunol. 190, 2614-2621. https://doi.org/10.4049/jimmunol.1202354
  14. Gottschalk, R.A., Corse, E., and Allison, J.P. (2010). TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J. Exp. Med. 207, 1701-1711. https://doi.org/10.1084/jem.20091999
  15. Grueter, B., Petter, M., Egawa, T., Laule-Kilian, K., Aldrian, C.J., Wuerch, A., Ludwig, Y., Fukuyama, H., Wardemann, H., and Waldschuetz, R., et al. (2005) Runx3 regulates integrin ${\alpha}_E$/CD103 and CD4 expression during development of $CD4^-$/$CD8^+$ T cells. J. Immunol. 175, 1694-1705. https://doi.org/10.4049/jimmunol.175.3.1694
  16. Hadley, G.A., Rostapshova, E.A., Gomolka, D.M., Taylor, B.M., Bartlett, S.T., Drachenberg, C.I., and Weir, M.R. (1999). Regulation of the epithelial cell-specific integrin, CD103, by human $CD8^+$ cytolytic T lymphocytes. Transplantation. 67, 1418-1425. https://doi.org/10.1097/00007890-199906150-00005
  17. Horwitz, D.A., Zheng, S.G., and Gray, J.D. (2008). Natural and TGF-${\beta}$-induced $Foxp3^+CD4^+$ $CD25^+$ regulatory T cells are not mirror images of each other. Trends Immunol. 29, 429-435. https://doi.org/10.1016/j.it.2008.06.005
  18. Huehn, J., Siegmund, K., Lehmann, J.C., Siewert, C., Haubold, U., Feuerer, M., Debes, G.F., Lauber, J, Frey, O, and Przybylski, G.K. (2004). Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like $CD4^+$ regulatory T cells. J. Exp. Med. 199, 303-313. https://doi.org/10.1084/jem.20031562
  19. Kang, B.H., Min, H.S., Lee, Y.J., Choi, B., Kim, E.J., Lee, J., Kim, J.R., Cho, K.H., Kim, T.J., and Jung, K.C., et al. (2015a). Analyses of the TCR repertoire of MHC class II-restricted innate $CD4^+$ T cells. Exp. Mol. Med. 47, e154. https://doi.org/10.1038/emm.2015.7
  20. Kang, B.H., Park, H.J., Yum, H.I., Park, S.P., Park, J.K., Kang, E.H., Lee, J.I., Lee, E.B., Park, C.G., and Jung, K.C., et al. (2015b). Thymic low affinity/avidity interaction selects natural Th1 cells. J. Immunol. 194, 5861-5871. https://doi.org/10.4049/jimmunol.1401628
  21. Karecla, P.I., Bowden, S.J., Green, S.J., and Kilshaw, P.J. (1995). Recognition of E-cadherin on epithelial cells by the mucosal T cell integrin ${\alpha}$M290 ${\beta}$7 (${\alpha}E{\beta}7$). Eur. J. Immunol. 25, 852-856. https://doi.org/10.1002/eji.1830250333
  22. Kilshaw, P.J., and Murant, S.J. (1991). Expression and regulation of ${\beta}$-7 (${\beta}$-P) integrins on mouse lymphocytes: relevance to the mucosal immune system. Eur. J. Immunol. 21, 2591-2597. https://doi.org/10.1002/eji.1830211041
  23. Lai, D., Zhu, J., Wang, T., Hu-Li, J., Terabe, M., Berzofsky, J.A., Clayberger, C., and Krensky, A.M. (2011). KLF13 sustains thymic memory-like $CD8^+$ T cells in BALB/c mice by regulating IL-4-generating invariant natural killer T cells. J. Exp. Med. 208, 1093-1103. https://doi.org/10.1084/jem.20101527
  24. Lee, Y.J., Jung, K.C., and Park, S.H. (2009). MHC class II-dependent T-T interactions create a diverse, functional and immunoregulatory reaction circle. Immunol. Cell. Biol. 87, 65-71. https://doi.org/10.1038/icb.2008.85
  25. Lee, Y.J., Jeon, Y.K., Kang, B.H., Chung, D.H., Park, C.G., Shin, H.Y., Jung, K.C., and Park, S.H. (2010). Generation of $PLZF^+$ $CD4^+$ T cells via MHC class II-dependent thymocyte-thymocyte interaction is a physiological process in humans. J. Exp. Med. 207, 237-246. https://doi.org/10.1084/jem.20091519
  26. Lee, Y.J., Holzapfel, K.L., Zhu, J., Jameson, S.C., and Hogquist, K.A. (2013). Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat. Immunol. 14, 1146-1154. https://doi.org/10.1038/ni.2731
  27. Lehmann, J., Huehn, J., de la Rosa, M., Maszyna, F., Kretschmer, U., Krenn, V., Brunner, M., Scheffold, A., and Hamann, A. (2002). Expression of the integrin ${\alpha}E{\beta}7$ identifies unique subsets of $CD25^+$ as well as $CD25^-$ regulatory T cells. Proc. Natl. Acad. Sci. USA 99, 13031-13036. https://doi.org/10.1073/pnas.192162899
  28. Li, M.O., and Flavell, R.A. (2008). TGF-${\beta}$: A master of all T cell trades. Cell 134, 392-404. https://doi.org/10.1016/j.cell.2008.07.025
  29. Li, W., Kim, M.G., Gourley, T.S., McCarthy, B.P., Sant'Angelo, D.B., and Chang, C.H. (2005). An alternate pathway for CD4 T cell development: thymocyte-expressed MHC class II selects a distinct T cell population. Immunity 23, 375-386. https://doi.org/10.1016/j.immuni.2005.09.002
  30. Li, W., Sofi, M.H., Rietdijk, S., Wang, N., Terhorst, C., and Chang, C.H. (2007). The SLAM-Associated protein signaling pathway is required for development of $CD4^+$ T cells selected by homotypic thymocyte interaction. Immunity 27, 763-774. https://doi.org/10.1016/j.immuni.2007.10.008
  31. Lio, C.W., and Hsieh, C.S. (2008). A two-step process for thymic regulatory T cell development. Immunity 28, 100-111. https://doi.org/10.1016/j.immuni.2007.11.021
  32. Liu, Y., Zhang, P., Li, J., Kulkarni, A.B., Perruche, S., and Chen, W. (2008). A critical function for TGF-${\beta}$ signaling in the development of natural $CD4^+CD25^+Foxp3^+$ regulatory T cells. Nat. Immunol. 9, 632-640. https://doi.org/10.1038/ni.1607
  33. Mackay, L.K., Rahimpour, A., Ma, J.Z., Collins, N., Stock, A.T., Hafon, M.L., Vega-Ramos, J., Lauzurica, P., Mueller, S.N., and Stefanovic, T., et al. (2013). The developmental pathway for $CD103^+CD8^+$ tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294-1301. https://doi.org/10.1038/ni.2744
  34. Maerten, P., Shen, C., Bullens, D.M., Van Assche, G., Van Gool, S., Geboes, K., Rutgeerts, P., and Ceuppens, J.L. (2005). Effects of interleukin 4 on $CD25^+$$CD4^+$ regulatory T cell function. J. Auto-immun. 25, 112-120.
  35. McHugh, R.S., Whitters, M.J., Piccirillo, C.A., Young, D.A., Shevach, E.M., Collins, M., and Byrne, M.C. (2002). $CD4^+CD25^+$ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311-323. https://doi.org/10.1016/S1074-7613(02)00280-7
  36. Min, H.S., Lee, Y.J., Jeon, Y.K., Kim, E.J., Kang, B.H., Jung, K.C., Chang, C.H., and Park, S.H. (2011). MHC Class II-restricted interaction between thymocytes plays an essential role in the production of innate $CD8^+$ T Cells. J. Immunol. 186, 5749-5757. https://doi.org/10.4049/jimmunol.1002825
  37. Ouyang, W., Beckett, O., Ma, Q., and Li, M.O. (2010). Transforming growth factor-${\beta}$ signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32, 642-653. https://doi.org/10.1016/j.immuni.2010.04.012
  38. Park, S.H., Bae, Y.M., Kim, T.J., Ha, I.S., Kim, S., Chi, J.G., and Lee, S.K. (1992). HLA-DR expression in human fetal thymocytes. Hum. Immunol. 33, 294-298. https://doi.org/10.1016/0198-8859(92)90338-N
  39. Park, J.H., Adoro, S., Guinter, T., Erman, B., Alag, A.S., Catalfamo, M., Kimura, M.Y., Cui, Y., Lucas, P.J., and Gress, R.E., et al. (2010). Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nat. Immunol. 11, 257-264. https://doi.org/10.1038/ni.1840
  40. Prince, A.L., Kraus, Z., Carty, S.A., Ng, C., Yin, C.C., Jordan, M.S., Schwartzberg, P.L., and Berg, L.J. (2014a). Alonzo, E.S., and Sant'Angelo, D.B. (2011). Development of PLZF-expressing innateT cells. Curr. Opin. Immunol. 23, 220-227.
  41. Prince, A.L., Watkin, L.B., Yin, C.C., Selin, L.K., Kang, J., Schwartzberg, P.L., and Berg, L.J. (2014b). Innate $PLZF^+CD4^+$ ${\alpha}{\beta}$ T cells develop and expand in the absence of Itk. J. Immunol. 193, 673-687. https://doi.org/10.4049/jimmunol.1302058
  42. Rao, P.E., Petrone, A.L., and Ponath, P.D. (2005). Differentiation and expansion of T cells with regulatory function from human peripheral lymphocytes by stimulation in the presence of TGF-${\beta}$. J. Immunol. 174, 1446-1455. https://doi.org/10.4049/jimmunol.174.3.1446
  43. Robertson, H., Wong, W.K., Talbot, D., Burt, A.D., and Kirby, J.A. (2001). Tubulitis after renal transplantation: demonstration of an association between $CD103^+$ T cells, transforming growth factor ${\beta}$1 expression and rejection grade. Transplantation 71, 306-313. https://doi.org/10.1097/00007890-200101270-00024
  44. Saito, K., Torii, M., Ma, N., Tsuchiya, T., Wang, L., Hori, T., Nagakubo, D., Nitta, N., Kanegasaki, S., and Hieshima, K. (2008). Differential regulatory function of resting and preactivated allergen-specific $CD4^+$ $CD25^+$ regulatory T cells in Th2-type airway inflammation. J. Immunol. 181, 6889-6897. https://doi.org/10.4049/jimmunol.181.10.6889
  45. Siewert, C., Lauer, U., Cording, S., Bopp, T., Schmitt, E., Hamann, A., and Huehn, J. (2008). Experience-driven development: effector/memory-like ${{\alpha}_E}^+Foxp3^+$ regulatory T cells originate from both naive T cells and naturally occurring naive-like regulatory T cells. J. Immunol. 180, 146-155. https://doi.org/10.4049/jimmunol.180.1.146
  46. Skapenko, A., Kalden, J.R., Lipsky, P.E., and Schulze-Koops, H. (2005). The IL-4 receptor ${\alpha}$-chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing $CD25^+CD4^+$ regulatory T cells from $CD25^-CD4^+$ precursors. J. Immunol. 775, 6107-6116.
  47. Stephens, G.L., Andersson, J., and Shevach, E.M. (2007). Distinct subsets of $Foxp3^+$ regulatory T cells participate in the control of immune responses. J. Immunol. 178, 6901-6911. https://doi.org/10.4049/jimmunol.178.11.6901
  48. Treiner, E., and Lantz, O. (2006). CD1d- and MR1-restricted invariant T cells: of mice and men. Curr. Opin. Immunol. 18, 519-526. https://doi.org/10.1016/j.coi.2006.07.001
  49. Vignali, D.A.A., Collison, L.W., and Workman, C.J. (2008). How regulatory T cells work. Nat. Rev. Immunol. 8, 523-532. https://doi.org/10.1038/nri2343
  50. Wang, D., Yuan, R., Feng, Y., El-Asady, R., Farber, D.L., Gress, R.E., Lucas, P.J., and Hadley, G.A. (2004). Regulation of CD103 expression by $CD8^+$ T cells responding to renal allografts. J. Immunol. 172, 214-221. https://doi.org/10.4049/jimmunol.172.1.214
  51. Wei, J., Duramad, O., Perng, O.A., Reiner, S.L., Liu, Y.J., and Qin, F.X. (2007). Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of $Foxp3^+$ regulatory T cells. Proc. Nat'l. Acad. Sci. USA 104, 18169-18174. https://doi.org/10.1073/pnas.0703642104
  52. Weinreich, M.A., Odumade, O.A., Jameson, S.C., and Hogquist, K.A. (2010). T cells expressing the transcription factor PLZF regulate the development of memory-like $CD8^+$ T cells. Nat. Immunol. 11, 709-716. https://doi.org/10.1038/ni.1898
  53. Zhao, D., Zhang, C., Yi, T., Lin, C.L., Todorov, I., Kandeel, F., Forman, S., and Zeng, D. (2008). In vivo-activated $CD103^+CD4^+$ regulatory T cells ameliorate ongoing chronic graft-versus-host disease. Blood 112, 2129-2138. https://doi.org/10.1182/blood-2008-02-140277

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