Characterization of CD8 T Cell Differentiation following SIVΔnef Vaccination by Transcription Factor Expression Profiling

English version České info

The live attenuated vaccine SIVΔnef can induce robust CD8+ T cell- mediated protection against infection with pathogenic SIV in macaques. Thus, there is substantial interest in characterizing these immune responses to inform HIV vaccine design. Animals challenged at 15–20 weeks post vaccination exhibit robust protection, whereas animals challenged at 5 weeks post-vaccination manifest little protection. Since the frequency of SIV-specific T cells decreases from week 5 to week 20, it is likely that the quality of the response to challenge changes as virus-specific cells differentiate. We applied a novel approach of transcription factor expression profiling to characterize the differences in SIV-specific cell function and phenotype at more protected and less protected time points. Using unsupervised clustering methods informed by expression profiles assessed in purified CD8+ T cell subsets, we show that SIV-specific cells display expression profiles different than any purified CD8+ T cell subset, and intermediate to sorted effector memory and central memory subsets. SIV-specific cells overall appear more effector memory-like at week 5 post-vaccination, and more central memory-like at week 20 post-vaccination. Distinct profiles of CD8+ T cells specific for different SIV epitopes having different immune escape kinetics suggests maturation is regulated by ongoing low-level replication of vaccine virus.

Vyšlo v časopise: Characterization of CD8 T Cell Differentiation following SIVΔnef Vaccination by Transcription Factor Expression Profiling. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004740
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004740

Souhrn

Zdroje

1. Daniel MD, Kirchhoff F, Czajak SC, Sehgal PK, Desrosiers RC (1992) Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 258: 1938–1941. 1470917

2. Almond N, Kent K, Cranage M, Rud E, Clarke B, et al. (1995) Protection by attenuated simian immunodeficiency virus in macaques against challenge with virus-infected cells. Lancet 345: 1342–1344. 7752758

3. Johnson RP, Lifson JD, Czajak SC, Cole KS, Manson KH, et al. (1999) Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: inverse relationship of degree of protection with level of attenuation. J Virol 73: 4952–4961. 10233957

4. Baba TW, Liska V, Khimani AH, Ray NB, Dailey PJ, et al. (1999) Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques. Nat Med 5: 194–203. 9930868

5. Baba TW, Jeong YS, Pennick D, Bronson R, Greene MF, et al. (1995) Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 267: 1820–1825. 7892606

6. Schmitz JE, Johnson RP, McClure HM, Manson KH, Wyand MS, et al. (2005) Effect of CD8+ lymphocyte depletion on virus containment after simian immunodeficiency virus SIVmac251 challenge of live attenuated SIVmac239delta3-vaccinated rhesus macaques. J Virol 79: 8131–8141. 15956558

7. Johnson RP, Glickman RL, Yang JQ, Kaur A, Dion JT, et al. (1997) Induction of vigorous cytotoxic T-lymphocyte responses by live attenuated simian immunodeficiency virus. J Virol 71: 7711–7718. 9311855

8. Gauduin MC, Glickman RL, Ahmad S, Yilma T, Johnson RP (1999) Immunization with live attenuated simian immunodeficiency virus induces strong type 1 T helper responses and beta-chemokine production. Proc Natl Acad Sci USA 96: 14031–14036. 10570193

9. Cole KS, Rowles JL, Jagerski BA, Murphey-Corb M, Unangst T, et al. (1997) Evolution of envelope-specific antibody responses in monkeys experimentally infected or immunized with simian immunodeficiency virus and its association with the development of protective immunity. J Virol 71: 5069–5079. 9188572

10. Li Q, Zeng M, Duan L, Voss JE, Smith AJ, et al. (2014) Live simian immunodeficiency virus vaccine correlate of protection: local antibody production and concentration on the path of virus entry. J Immunol 193: 3113–3125. doi: 10.4049/jimmunol.1400820 25135832

11. Metzner KJ, Jin X, Lee FV, Gettie A, Bauer DE, et al. (2000) Effects of in vivo CD8(+) T cell depletion on virus replication in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine. J Exp Med 191: 1921–1931. 10839807

12. Sasikala-Appukuttan AK, Kim HO, Kinzel NJ, Hong JJ, Smith AJ, et al. (2013) Location and Dynamics of the Immunodominant CD8 T Cell Response to SIVDeltanef Immunization and SIVmac251 Vaginal Challenge. PLoS One 8: e81623. doi: 10.1371/journal.pone.0081623 24349100

13. Fukazawa Y, Park H, Cameron MJ, Lefebvre F, Lum R, et al. (2012) Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines. Nat Med 18: 1673–1681. doi: 10.1038/nm.2934 22961108

14. Salisch NC, Kaufmann DE, Awad AS, Reeves RK, Tighe DP, et al. (2010) Inhibitory TCR coreceptor PD-1 is a sensitive indicator of low-level replication of SIV and HIV-1. J Immunol 184: 476–487. doi: 10.4049/jimmunol.0902781 19949078

15. Cromwell MA, Veazey RS, Altman JD, Mansfield KG, Glickman R, et al. (2000) Induction of mucosal homing virus-specific CD8(+) T lymphocytes by attenuated simian immunodeficiency virus. J Virol 74: 8762–8766. 10954580

16. Horton H, Vogel TU, Carter DK, Vielhuber K, Fuller DH, et al. (2002) Immunization of rhesus macaques with a DNA prime/modified vaccinia virus Ankara boost regimen induces broad simian immunodeficiency virus (SIV)-specific T-cell responses and reduces initial viral replication but does not prevent disease progression following challenge with pathogenic SIVmac239. J Virol 76: 7187–7202. 12072518

17. Hanke T, Samuel RV, Blanchard TJ, Neumann VC, Allen TM, et al. (1999) Effective induction of simian immunodeficiency virus-specific cytotoxic T lymphocytes in macaques by using a multiepitope gene and DNA prime-modified vaccinia virus Ankara boost vaccination regimen. J Virol 73: 7524–7532. 10438842

18. Connor RI, Montefiori DC, Binley JM, Moore JP, Bonhoeffer S, et al. (1998) Temporal analyses of virus replication, immune responses, and efficacy in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine. J Virol 72: 7501–7509. 9696847

19. Kirchhoff F, Kestler HWI, Desrosiers RC (1994) Upstream U3 sequences in simian immunodeficiency virus are selectively deleted in vivo in the absence of an intact nef gene. J Virol 68: 2031–2037. 8107267

20. Kestler HW III, Ringler DJ, Mori K, Panicali DL, Sehgal PK, et al. (1991) Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 65: 651–662. 2032289

21. Burwitz BJ, Ende Z, Sudolcan B, Reynolds MR, Greene JM, et al. (2011) Simian Immunodeficiency Virus SIVmac239{Delta}nef Vaccination Elicits Different Tat28–35SL8-Specific CD8+ T-Cell Clonotypes Compared to a DNA Prime/Adenovirus Type 5 Boost Regimen in Rhesus Macaques. J Virol 85: 3683–3689. doi: 10.1128/JVI.02112-10 21270159

22. Kaech SM, Cui W (2012) Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 12: 749–761. doi: 10.1038/nri3307 23080391

23. Vaquerizas JM, Kummerfeld SK, Teichmann SA, Luscombe NM (2009) A census of human transcription factors: function, expression and evolution. Nat Rev Genet 10: 252–263. doi: 10.1038/nrg2538 19274049

24. Novershtern N, Subramanian A, Lawton LN, Mak RH, Haining WN, et al. (2011) Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 144: 296–309. doi: 10.1016/j.cell.2011.01.004 21241896

25. Levine M, Tjian R (2003) Transcription regulation and animal diversity. Nature 424: 147–151. 12853946

26. Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, et al. (2012) Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37: 1130–1144. doi: 10.1016/j.immuni.2012.08.021 23159438

27. Ravasi T, Suzuki H, Cannistraci CV, Katayama S, Bajic VB, et al. (2010) An atlas of combinatorial transcriptional regulation in mouse and man. Cell 140: 744–752. doi: 10.1016/j.cell.2010.01.044 20211142

28. Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT, et al. (2005) Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol 6: 1236–1244. 16273099

29. Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, et al. (2007) Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 27: 281–295. 17723218

30. Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, et al. (2003) Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302: 1041–1043. 14605368

31. Takemoto N, Intlekofer AM, Northrup JT, Wherry EJ, Reiner SL (2006) Cutting Edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation. J Immunol 177: 7515–7519. 17114419

32. Kallies A, Xin A, Belz GT, Nutt SL (2009) Blimp-1 transcription factor is required for the differentiation of effector CD8(+) T cells and memory responses. Immunity 31: 283–295. doi: 10.1016/j.immuni.2009.06.021 19664942

33. Rutishauser RL, Martins GA, Kalachikov S, Chandele A, Parish IA, et al. (2009) Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31: 296–308. doi: 10.1016/j.immuni.2009.05.014 19664941

34. Yang CY, Best JA, Knell J, Yang E, Sheridan AD, et al. (2011) The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat Immunol 12: 1221–1229. doi: 10.1038/ni.2158 22057289

35. Cannarile MA, Lind NA, Rivera R, Sheridan AD, Camfield KA, et al. (2006) Transcriptional regulator Id2 mediates CD8+ T cell immunity. Nat Immunol 7: 1317–1325. 17086188

36. Masson F, Minnich M, Olshansky M, Bilic I, Mount AM, et al. (2013) Id2-mediated inhibition of E2A represses memory CD8+ T cell differentiation. J Immunol 190: 4585–4594. doi: 10.4049/jimmunol.1300099 23536629

37. Kuroda S, Yamazaki M, Abe M, Sakimura K, Takayanagi H, et al. (2011) Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression. Proc Natl Acad Sci U S A 108: 14885–14889. doi: 10.1073/pnas.1105133108 21873234

38. Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, et al. (2010) Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med 16: 1147–1151. doi: 10.1038/nm.2232 20890291

39. Kurachi M, Barnitz RA, Yosef N, Odorizzi PM, DiIorio MA, et al. (2014) The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells. Nat Immunol 15: 373–383. doi: 10.1038/ni.2834 24584090

40. Cruz-Guilloty F, Pipkin ME, Djuretic IM, Levanon D, Lotem J, et al. (2009) Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med 206: 51–59. doi: 10.1084/jem.20081242 19139168

41. Zhang S, Rozell M, Verma RK, Albu DI, Califano D, et al. (2010) Antigen-specific clonal expansion and cytolytic effector function of CD8+ T lymphocytes depend on the transcription factor Bcl11b. J Exp Med 207: 1687–1699. doi: 10.1084/jem.20092136 20660613

42. Vanvalkenburgh J, Albu DI, Bapanpally C, Casanova S, Califano D, et al. (2011) Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease. J Exp Med 208: 2069–2081. doi: 10.1084/jem.20102683 21875956

43. Kastner P, Chan S, Vogel WK, Zhang LJ, Topark-Ngarm A, et al. (2010) Bcl11b represses a mature T-cell gene expression program in immature CD4(+)CD8(+) thymocytes. Eur J Immunol 40: 2143–2154. doi: 10.1002/eji.200940258 20544728

44. Willinger T, Freeman T, Herbert M, Hasegawa H, McMichael AJ, et al. (2006) Human naive CD8 T cells down-regulate expression of the WNT pathway transcription factors lymphoid enhancer binding factor 1 and transcription factor 7 (T cell factor-1) following antigen encounter in vitro and in vivo. J Immunol 176: 1439–1446. 16424171

45. Zhou X, Yu S, Zhao DM, Harty JT, Badovinac VP, et al. (2010) Differentiation and persistence of memory CD8(+) T cells depend on T cell factor 1. Immunity 33: 229–240. doi: 10.1016/j.immuni.2010.08.002 20727791

46. Best JA, Blair DA, Knell J, Yang E, Mayya V, et al. (2013) Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation. Nat Immunol 14: 404–412. doi: 10.1038/ni.2536 23396170

47. Billerbeck E, Kang YH, Walker L, Lockstone H, Grafmueller S, et al. (2010) Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties. Proc Natl Acad Sci U S A 107: 3006–3011. doi: 10.1073/pnas.0914839107 20133607

48. Tai TS, Pai SY, Ho IC (2013) GATA-3 regulates the homeostasis and activation of CD8+ T cells. J Immunol 190: 428–437. doi: 10.4049/jimmunol.1201361 23225883

49. Curtis MM, Way SS, Wilson CB (2009) IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons. J Immunol 183: 381–387. doi: 10.4049/jimmunol.0900939 19542449

50. Johnson RP, Desrosiers RC (1998) Protective immunity induced by live attenuated SIV. Curr Opp Immunol 10: 436–443. 9722920

51. Barouch DH, Kunstman J, Kuroda MJ, Schmitz JE, Santra S, et al. (2002) Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415: 335–339. 11797012

52. Allen TM, O'Connor DH, Jing P, Dzuris JL, Mothe BR, et al. (2000) Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407: 386–390. 11014195

53. Bimber BN, Burwitz BJ, O'Connor S, Detmer A, Gostick E, et al. (2009) Ultradeep pyrosequencing detects complex patterns of CD8+ T-lymphocyte escape in simian immunodeficiency virus-infected macaques. J Virol 83: 8247–8253. doi: 10.1128/JVI.00897-09 19515775

54. Huynh KD, Fischle W, Verdin E, Bardwell VJ (2000) BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev 14: 1810–1823. 10898795

55. Ichii H, Sakamoto A, Hatano M, Okada S, Toyama H, et al. (2002) Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells. Nat Immunol 3: 558–563. 12021781

56. Nayar R, Enos M, Prince A, Shin H, Hemmers S, et al. (2012) TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation. Proc Natl Acad Sci U S A 109: E2794–2802. doi: 10.1073/pnas.1205742109 23011795

57. Jameson SC, Masopust D (2009) Diversity in T cell memory: an embarrassment of riches. Immunity 31: 859–871. doi: 10.1016/j.immuni.2009.11.007 20064446

58. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401: 708–712. 10537110

59. Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22: 745–763. 15032595

60. Pitcher CJ, Hagen SI, Walker JM, Lum R, Mitchell BL, et al. (2002) Development and homeostasis of T cell memory in rhesus macaque. J Immunol 168: 29–43. 11751943

61. Crotty S, Johnston RJ, Schoenberger SP (2010) Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol 11: 114–120. doi: 10.1038/ni.1837 20084069

62. Wherry EJ (2011) T cell exhaustion. Nat Immunol 12: 492–499. 21739672

63. Youngblood B, Wherry EJ, Ahmed R (2012) Acquired transcriptional programming in functional and exhausted virus-specific CD8 T cells. Curr Opin HIV AIDS 7: 50–57. doi: 10.1097/COH.0b013e32834ddcf2 22134341

64. Hong JJ, Amancha PK, Rogers K, Ansari AA, Villinger F (2013) Re-evaluation of PD-1 expression by T cells as a marker for immune exhaustion during SIV infection. PLoS One 8: e60186. doi: 10.1371/journal.pone.0060186 23555918

65. Genesca M, Skinner PJ, Hong JJ, Li J, Lu D, et al. (2008) With minimal systemic T-cell expansion, CD8+ T Cells mediate protection of rhesus macaques immunized with attenuated simian-human immunodeficiency virus SHIV89.6 from vaginal challenge with simian immunodeficiency virus. J Virol 82: 11181–11196. doi: 10.1128/JVI.01433-08 18787003

66. Genesca M, Skinner PJ, Bost KM, Lu D, Wang Y, et al. (2008) Protective attenuated lentivirus immunization induces SIV-specific T cells in the genital tract of rhesus monkeys. Mucosal Immunol 1: 219–228. doi: 10.1038/mi.2008.6 19079181

67. Genesca M, Rourke T, Li J, Bost K, Chohan B, et al. (2007) Live attenuated lentivirus infection elicits polyfunctional simian immunodeficiency virus Gag-specific CD8+ T cells with reduced apoptotic susceptibility in rhesus macaques that control virus replication after challenge with pathogenic SIVmac239. Journal of Immunology 179: 4732–4740. 17878372

68. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, et al. (2006) HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107: 4781–4789. 16467198

69. Chen H, Piechocka-Trocha A, Miura T, Brockman MA, Julg BD, et al. (2009) Differential neutralization of human immunodeficiency virus (HIV) replication in autologous CD4 T cells by HIV-specific cytotoxic T lymphocytes. J Virol 83: 3138–3149. doi: 10.1128/JVI.02073-08 19158248

70. Julg B, Williams KL, Reddy S, Bishop K, Qi Y, et al. (2010) Enhanced anti-HIV functional activity associated with Gag-specific CD8 T-cell responses. J Virol 84: 5540–5549. doi: 10.1128/JVI.02031-09 20335261

71. Saez-Cirion A, Lacabaratz C, Lambotte O, Versmisse P, Urrutia A, et al. (2007) HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci U S A 104: 6776–6781. 17428922

72. Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, et al. (2002) HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nature Immunology 3: 1061–1068. 12368910

73. Ndhlovu ZM, Proudfoot J, Cesa K, Alvino DM, McMullen A, et al. (2012) Elite controllers with low to absent effector CD8+ T cell responses maintain highly functional, broadly directed central memory responses. J Virol 86: 6959–6969. doi: 10.1128/JVI.00531-12 22514340

74. Ndhlovu ZM, Chibnik LB, Proudfoot J, Vine S, McMullen A, et al. (2013) High-dimensional immunomonitoring models of HIV-1-specific CD8 T-cell responses accurately identify subjects achieving spontaneous viral control. Blood 121: 801–811. doi: 10.1182/blood-2012-06-436295 23233659

75. Cline AN, Bess JW, Piatak M Jr., Lifson JD (2005) Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations, and application to reverse engineering of vaccines for AIDS. J Med Primatol 34: 303–312. 16128925

76. Allen TM, Sidney J, delGuercio M-F, Glickman RL, Lensmeyer GL, et al. (1998) Characterization of the peptide binding motif of a rhesus MHC class I molecule (Mamu-A*01) that binds an immunodominant CTL epitope from SIV. J Immunol 160: 6062–6071. 9637523

77. Allen TM, Mothe BR, Sidney J, Jing P, Dzuris JL, et al. (2001) CD8(+) lymphocytes from simian immunodeficiency virus-infected rhesus macaques recognize 14 different epitopes bound by the major histocompatibility complex class I molecule mamu-A*01: implications for vaccine design and testing. J Virol 75: 738–749. 11134287

78. Kuroda M, Schmitz JE, Barouch DH, Craiu A, Allen TM, et al. (1998) Analysis of gag-specific cytotoxic T lymphocytes in simian immunodeficiency virus-infected rhesus monkeys by cell staining with a tetrameric major histocompatibility complex class I-peptide complex. J Exp Med 187: 1373–1381. 9565630

79. R Core Team (2014) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3–900051–07–0, URL http://www.R-project.org/.

80. Neuwirth E (2011) RColorBrewer: ColorBrewer palettes. R package version 1.0–5. http://CRAN.R-project.org/package=RColorBrewer.

81. Lemon J (2006) Plotrix: a package in the red light district of R. R-News, 6(4): 8–12.

82. Warnes GR, Bolker B, Bonebakker L, Gentleman R, Huber W, et al. (2014) gplots: Various R programming tools for plotting data. R package version 2.13.0. http://CRAN.R-project.org/package=gplots.

83. Bates D, Maechler M, Bolker B, Walker S (2014) lme4: Linear mixed-effects models using Eigen and S4. R package version 1.1–6. http://CRAN.R-project.org/package=lme4.

84. Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, et al. (2011) Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334: 1561–1565. doi: 10.1126/science.1214914 22033518

85. Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, et al. (2011) Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147: 629–640. doi: 10.1016/j.cell.2011.09.025 21999944

86. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, et al. (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27: 670–684. 17950003

87. Berkes CA, Bergstrom DA, Penn BH, Seaver KJ, Knoepfler PS, et al. (2004) Pbx marks genes for activation by MyoD indicating a role for a homeodomain protein in establishing myogenic potential. Mol Cell 14: 465–477. 15149596

88. Cretney E, Xin A, Shi W, Minnich M, Masson F, et al. (2011) The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 12: 304–311. doi: 10.1038/ni.2006 21378976

89. Mittrucker HW, Matsuyama T, Grossman A, Kundig TM, Potter J, et al. (1997) Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275: 540–543. 8999800

90. Zhang W, Zhang J, Kornuc M, Kwan K, Frank R, et al. (1995) Molecular cloning and characterization of NF-IL3A, a transcriptional activator of the human interleukin-3 promoter. Mol Cell Biol 15: 6055–6063. 7565758

91. Fuchs A, Vermi W, Lee JS, Lonardi S, Gilfillan S, et al. (2013) Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity 38: 769–781. doi: 10.1016/j.immuni.2013.02.010 23453631