Rho-GTPases as key regulators of T-lymphocyte biology

Small GTPases

Volumn 5, Issue MAY, 2014, Pages

  Saoudi, Abdelhadi ^a,b,c   Kassem, Sahar ^a,b,c   Dejean, Aanne ^a,b,c   Gaud, Guillaume ^a,b,c  

^a INSERM   (France)

^b CNRS   (France)

^c UNIVERSITÉ DE TOULOUSE   (France)

Author keywords

Rho GTPases; T cell development; T cell differentiation; T cell migration

Indexed keywords

RHO GUANINE NUCLEOTIDE BINDING PROTEIN; T LYMPHOCYTE RECEPTOR; CALCINEURIN; EZRIN; GAMMA INTERFERON; MITOGEN ACTIVATED PROTEIN KINASE; MOESIN; PROTEIN CDC42; PROTEIN KINASE ZAP 70; RADIXIN; STRESS ACTIVATED PROTEIN KINASE; SYNAPTOPHYSIN; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTION FACTOR NFAT;

CELL MATURATION; COMPLEX FORMATION; CYTOKINE PRODUCTION; CYTOLOGY; ENZYME ACTIVITY; HUMAN; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOLOGICAL SYNAPSE; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE MIGRATION; NONHUMAN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; THYMOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; IMMUNOREGULATION; LYMPHOCYTE PROLIFERATION; REGULATORY T LYMPHOCYTE;

EID: 84901379372     PISSN: 21541248     EISSN: 21541256     Source Type: Journal    
DOI: 10.4161/sgtp.28208     Document Type: Review

References (92)

1. Van Aelst L, D'Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev 1997; 11:2295-322; PMID:9308960; http://dx.doi.org/10.1101/gad.11.18.2295
2. Zheng Y. Dbl family guanine nucleotide exchange factors. Trends Biochem Sci 2001; 26:724-32; PMID:11738596; http://dx.doi.org/10.1016/S0968-0004(01)01973-9
3. Moon SY, Zheng Y. Rho GTPase-activating proteins in cell regulation. Trends Cell Biol 2003; 13:13-22; PMID:12480336; http://dx.doi.org/10.1016/S0962-8924(02)00004-1
4. Olofsson B. Rho guanine dissociation inhibitors: pivotal molecules in cellular signalling. Cell Signal 1999; 11:545-54; PMID:10433515; http://dx.doi.org/10.1016/S0898-6568(98)00063-1
5. Wennerberg K, Der CJ. Rho-family GTPases: it's not only Rac and Rho (and I like it). J Cell Sci 2004; 117:1301-12; PMID:15020670; http://dx.doi.org/10.1242/jcs.01118
6. Aspenström P, Ruusala A, Pacholsky D. Taking Rho GTPases to the next level: the cellular functions of atypical Rho GTPases. Exp Cell Res 2007; 313:3673-9; PMID:17850788; http://dx.doi.org/10.1016/j.yexcr.2007.07.022
7. Rossman KL, Der CJ, Sondek J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 2005; 6:167-80; PMID:15688002; http://dx.doi.org/10.1038/nrm1587
8. Tcherkezian J, Lamarche-Vane N. Current knowledge of the large RhoGAP family of proteins. Biol Cell 2007; 99:67-86; PMID:17222083; http://dx.doi.org/10.1042/BC20060086
9. DerMardirossian C, Bokoch GM. GDIs: central regulatory molecules in Rho GTPase activation. Trends Cell Biol 2005; 15:356-63; PMID:15921909; http://dx.doi.org/10.1016/j.tcb.2005.05.001
10. Wang L, Zheng Y. Cell type-specific functions of Rho GTPases revealed by gene targeting in mice. Trends Cell Biol 2007; 17:58-64; PMID:17161947; http://dx.doi.org/10.1016/j.tcb.2006.11.009
11. Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 2008; 9:690-701; PMID:18719708; http://dx.doi.org/10.1038/nrm2476
12. Tybulewicz VL, Henderson RB. Rho family GTPases and their regulators in lymphocytes. Nat Rev Immunol 2009; 9:630-44; PMID:19696767; http://dx.doi.org/10.1038/nri2606
13. Rougerie P, Delon J. Rho GTPases: masters of T lymphocyte migration and activation. Immunol Lett 2012; 142:1-13; PMID:22207038; http://dx.doi.org/10.1016/j.imlet.2011.12.003
14. Ciofani M, Zúñiga-Pflücker JC. The thymus as an inductive site for T lymphopoiesis. Annu Rev Cell Dev Biol 2007; 23:463-93; PMID:17506693; http://dx.doi.org/10.1146/annurev.cellbio.23.090506.123547
15. von Boehmer H, Aifantis I, Feinberg J, Lechner O, Saint-Ruf C, Walter U, Buer J, Azogui O. Pleiotropic changes controlled by the pre-T-cell receptor. Curr Opin Immunol 1999; 11:135-42; PMID:10322152; http://dx.doi.org/10.1016/S0952-7915(99)80024-7
16. Fehling HJ, von Boehmer H. Early alpha beta T cell development in the thymus of normal and genetically altered mice. Curr Opin Immunol 1997; 9:263-75; PMID:9099797; http://dx.doi.org/10.1016/S0952-7915(97)80146-X
17. Aifantis I, Mandal M, Sawai K, Ferrando A, Vilimas T. Regulation of T-cell progenitor survival and cell-cycle entry by the pre-T-cell receptor. Immunol Rev 2006; 209:159-69; PMID:16448541; http://dx.doi.org/10.1111/j.0105-2896.2006.00343.x
18. Jameson SC, Bevan MJ. T-cell selection. Curr Opin Immunol 1998; 10:214-9; PMID:9602311; http://dx.doi.org/10.1016/S0952-7915(98)80251-3
19. Sebzda E, Mariathasan S, Ohteki T, Jones R, Bachmann MF, Ohashi PS. Selection of the T cell repertoire. Annu Rev Immunol 1999; 17:829-74; PMID:10358775; http://dx.doi.org/10.1146/annurev.immunol.17.1.829
20. Germain RN. T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol 2002; 2:309-22; PMID:12033737; http://dx.doi.org/10.1038/nri798
21. Na S, Li B, Grewal IS, Enslen H, Davis RJ, Hanke JH, Flavell RA. Expression of activated CDC42 induces T cell apoptosis in thymus and peripheral lymph organs via different pathways. Oncogene 1999; 18:7966-74; PMID:10637507; http://dx.doi.org/10.1038/sj.onc.1203122
22. Galandrini R, Henning SW, Cantrell DA. Different functions of the GTPase Rho in prothymocytes and late pre-T cells. Immunity 1997; 7:163-74; PMID:9252129; http://dx.doi.org/10.1016/S1074-7613(00)80519-1
23. Henning SW, Galandrini R, Hall A, Cantrell DA. The GTPase Rho has a critical regulatory role in thymus development. EMBO J 1997; 16:2397-407; PMID:9171353; http://dx.doi.org/10.1093/emboj/16.9.2397
24. Gomez M, Tybulewicz V, Cantrell DA. Control of pre-T cell proliferation and differentiation by the GTPase Rac-I. Nat Immunol 2000; 1:348-52; PMID:11017108; http://dx.doi.org/10.1038/79808
25. Crespo P, Schuebel KE, Ostrom AA, Gutkind JS, Bustelo XR. Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product. Nature 1997; 385:169-72; PMID:8990121; http://dx.doi.org/10.1038/385169a0
26. Bustelo XR. Regulatory and signaling properties of the Vav family. Mol Cell Biol 2000; 20:1461-77; PMID:10669724; http://dx.doi.org/10.1128/MCB.20.5.1461-1477.2000
27. Rapley J, Tybulewicz VL, Rittinger K. Crucial structural role for the PH and C1 domains of the Vav1 exchange factor. EMBO Rep 2008; 9:655-61; PMID:18511940; http://dx.doi.org/10.1038/embor.2008.80
28. Fischer KD, Zmuldzinas A, Gardner S, Barbacid M, Bernstein A, Guidos C. Defective T-cell receptor signalling and positive selection of Vav-deficient CD4+ CD8+ thymocytes. Nature 1995; 374:474-7; PMID:7700360; http://dx.doi.org/10.1038/374474a0
29. Tarakhovsky A, Turner M, Schaal S, Mee PJ, Duddy LP, Rajewsky K, Tybulewicz VL. Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav. Nature 1995; 374:467-70; PMID:7700358; http://dx.doi.org/10.1038/374467a0
30. Turner M, Mee PJ, Walters AE, Quinn ME, Mellor AL, Zamoyska R, Tybulewicz VL. A requirement for the Rho-family GTP exchange factor Vav in positive and negative selection of thymocytes. Immunity 1997; 7:451-60; PMID:9354466; http://dx.doi.org/10.1016/S1074-7613(00)80367-2
31. Zhang R, Alt FW, Davidson L, Orkin SH, Swat W. Defective signalling through the T-and B-cell antigen receptors in lymphoid cells lacking the vav proto-oncogene. Nature 1995; 374:470-3; PMID:7700359; http://dx.doi.org/10.1038/374470a0
32. Saveliev A, Vanes L, Ksionda O, Rapley J, Smerdon SJ, Rittinger K, Tybulewicz VL. Function of the nucleotide exchange activity of vav1 in T cell development and activation. Sci Signal 2009; 2:ra83; PMID:20009105; http://dx.doi.org/10.1126/scisignal.2000420
33. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature 2002; 420:629-35; PMID:12478284; http://dx.doi.org/10.1038/nature01148
34. Hall A. Rho GTPases and the actin cytoskeleton. Science 1998; 279:509-14; PMID:9438836; http://dx.doi.org/10.1126/science.279.5350.509
35. Vigorito E, Bell S, Hebeis BJ, Reynolds H, McAdam S, Emson PC, McKenzie A, Turner M. Immunological function in mice lacking the Rac-related GTPase RhoG. Mol Cell Biol 2004; 24:719-29; PMID:14701744; http://dx.doi.org/10.1128/MCB.24.2.719-729.2004
36. Sugihara K, Nakatsuji N, Nakamura K, Nakao K, Hashimoto R, Otani H, Sakagami H, Kondo H, Nozawa S, Aiba A, etal. Rac1 is required for the formation of three germ layers during gastrulation. Oncogene 1998; 17:3427-33; PMID:10030666; http://dx.doi.org/10.1038/sj.onc.1202595
37. Dumont C, Corsoni-Tadrzak A, Ruf S, de Boer J, Williams A, Turner M, Kioussis D, Tybulewicz VL. Rac GTPases play critical roles in early T-cell development. Blood 2009; 113:3990-8; PMID:19088377; http://dx.doi.org/10.1182/blood-2008-09-181180
38. Guo F, Cancelas JA, Hildeman D, Williams DA, Zheng Y. Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development. Blood 2008; 112:1767-75; PMID:18579797; http://dx.doi.org/10.1182/blood-2008-01-132068
39. Chen F, Ma L, Parrini MC, Mao X, Lopez M, Wu C, Marks PW, Davidson L, Kwiatkowski DJ, Kirchhausen T, etal. Cdc42 is required for PIP(2)-induced actin polymerization and early development but not for cell viability. Curr Biol 2000; 10:758-65; PMID:10898977; http://dx.doi.org/10.1016/S0960-9822(00)00571-6
40. Guo F, Hildeman D, Tripathi P, Velu CS, Grimes HL, Zheng Y. Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis. Proc Natl Acad Sci U S A 2010; 107:18505-10; PMID:20937872; http://dx.doi.org/10.1073/pnas.1010249107
41. Guo F, Zhang S, Tripathi P, Mattner J, Phelan J, Sproles A, Mo J, Wills-Karp M, Grimes HL, Hildeman D, etal. Distinct roles of Cdc42 in thymopoiesis and effector and memory T cell differentiation. PLoS One 2011; 6:e18002; PMID:21455314; http://dx.doi.org/10.1371/journal.pone.0018002
42. Hakem A, Sanchez-Sweatman O, You-Ten A, Duncan G, Wakeham A, Khokha R, Mak TW. RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev 2005; 19:1974-9; PMID:16107613; http://dx.doi.org/10.1101/gad.1310805
43. Liu AX, Rane N, Liu JP, Prendergast GC. RhoB is dispensable for mouse development, but it modifies susceptibility to tumor formation as well as cell adhesion and growth factor signaling in transformed cells. Mol Cell Biol 2001; 21:6906-12; PMID:11564874; http://dx.doi.org/10.1128/MCB.21.20.6906-6912.2001
44. Gu Y, Jasti AC, Jansen M, Siefring JE. RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells. Blood 2005; 105:1467-75; PMID:15494435; http://dx.doi.org/10.1182/blood-2004-04-1604
45. Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B. The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol 2002; 22:1158-71; PMID:11809807; http://dx.doi.org/10.1128/MCB.22.4.1158-1171.2002
46. Dorn T, Kuhn U, Bungartz G, Stiller S, Bauer M, Ellwart J, Peters T, Scharffetter-Kochanek K, Semmrich M, Laschinger M, etal. RhoH is important for positive thymocyte selection and T-cell receptor signaling. Blood 2007; 109:2346-55; PMID:17119112; http://dx.doi.org/10.1182/blood-2006-04-019034
47. Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA, Rho H. RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol 2006; 7:1182-90; PMID:17028588; http://dx.doi.org/10.1038/ni1396
48. Oda H, Tamehiro N, Patrick MS, Hayakawa K, Suzuki H. Differential requirement for RhoH in development of TCRαβ CD8αα IELs and other types of T cells. Immunol Lett 2013; 151:1-9; PMID:23499578; http://dx.doi.org/10.1016/j.imlet.2013.02.007
49. Wang H, Zeng X, Fan Z, Lim B. RhoH modulates pre-TCR and TCR signalling by regulating LCK. Cell Signal 2011; 23:249-58; PMID:20851766; http://dx.doi.org/10.1016/j.cellsig.2010.09.009
50. Bromley SK, Mempel TR, Luster AD. Orchestrating the orchestrators: chemokines in control of T cell traffic. Nat Immunol 2008; 9:970-80; PMID:18711434; http://dx.doi.org/10.1038/ni.f.213
51. Lafouresse F, Vasconcelos Z, Cotta-de-Almeida V, Dupré L. Actin cytoskeleton control of the comings and goings of T lymphocytes. Tissue Antigens 2013; 82:301-11; PMID:24131017; http://dx.doi.org/10.1111/tan.12193
52. Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996; 272:60-6; PMID:8600538; http://dx.doi.org/10.1126/science.272.5258.60
53. Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 2005; 21:247-69; PMID:16212495; http://dx.doi.org/10.1146/annurev.cellbio.21.020604.150721
54. Sánchez-Madrid F, del Pozo MA. Leukocyte polarization in cell migration and immune interactions. EMBO J 1999; 18:501-11; PMID:9927410; http://dx.doi.org/10.1093/emboj/18.3.501
55. Ratner S, Sherrod WS, Lichlyter D. Microtubule retraction into the uropod and its role in T cell polarization and motility. J Immunol 1997; 159:1063-7; PMID:9233597
56. Dustin ML. Visualization of cell-cell interaction contacts-synapses and kinapses. Adv Exp Med Biol 2008; 640:164-82; PMID:19065791; http://dx.doi.org/10.1007/978-0-387-09789-3_13
57. Krummel MF, Macara I. Maintenance and modulation of T cell polarity. Nat Immunol 2006; 7:1143-9; PMID:17053799; http://dx.doi.org/10.1038/ni1404
58. Stowers L, Yelon D, Berg LJ, Chant J. Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42. Proc Natl Acad Sci U S A 1995; 92:5027-31; PMID:7761442; http://dx.doi.org/10.1073/pnas.92.11.5027
59. García-Bernal D, Wright N, Sotillo-Mallo E, Nombela-Arrieta C, Stein JV, Bustelo XR, Teixidó J. Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin alpha4beta1. Mol Biol Cell 2005; 16:3223-35; PMID:15872091; http://dx.doi.org/10.1091/mbc.E04-12-1049
60. Croker BA, Handman E, Hayball JD, Baldwin TM, Voigt V, Cluse LA, Yang FC, Williams DA, Roberts AW. Rac2-deficient mice display perturbed T-cell distribution and chemotaxis, but only minor abnormalities in T(H)1 responses. Immunol Cell Biol 2002; 80:231-40; PMID:12067410; http://dx.doi.org/10.1046/j.1440-1711.2002.01077.x
61. Faroudi M, Hons M, Zachacz A, Dumont C, Lyck R, Stein JV, Tybulewicz VL. Critical roles for Rac GTPases in T-cell migration to and within lymph nodes. Blood 2010; 116:5536-47; PMID:20870900; http://dx.doi.org/10.1182/blood-2010-08-299438
62. Giagulli C, Scarpini E, Ottoboni L, Narumiya S, Butcher EC, Constantin G, Laudanna C. RhoA and zeta PKC control distinct modalities of LFA-1 activation by chemokines: critical role of LFA-1 affinity triggering in lymphocyte in vivo homing. Immunity 2004; 20:25-35; PMID:14738762; http://dx.doi.org/10.1016/S1074-7613(03)00350-9
63. Cherry LK, Li X, Schwab P, Lim B, Klickstein LB. RhoH is required to maintain the integrin LFA-1 in a nonadhesive state on lymphocytes. Nat Immunol 2004; 5:961-7; PMID:15300248; http://dx.doi.org/10.1038/ni1103
64. Baker CM, Comrie WA, Hyun YM, Chung HL, Fedorchuk CA, Lim K, Brakebusch C, McGrath JL, Waugh RE, Meier-Schellersheim M, etal. Opposing roles for RhoH GTPase during T-cell migration and activation. Proc Natl Acad Sci U S A 2012; 109:10474-9; PMID:22689994; http://dx.doi.org/10.1073/pnas.1114214109
65. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML. The immunological synapse: a molecular machine controlling T cell activation. Science 1999; 285:221-7; PMID:10398592; http://dx.doi.org/10.1126/science.285.5425.221
66. Singleton KL, Roybal KT, Sun Y, Fu G, Gascoigne NR, van Oers NS, Wülfing C. Spatiotemporal patterning during T cell activation is highly diverse. Sci Signal 2009; 2:ra15; PMID:19351954; http://dx.doi.org/10.1126/scisignal.2000199
67. Tskvitaria-Fuller I, Seth A, Mistry N, Gu H, Rosen MK, Wülfing C. Specific patterns of Cdc42 activity are related to distinct elements of T cell polarization. J Immunol 2006; 177:1708-20; PMID:16849480; http://dx.doi.org/10.4049/jimmunol.177.3.1708
68. Faure S, Salazar-Fontana LI, Semichon M, Tybulewicz VL, Bismuth G, Trautmann A, Germain RN, Delon J. ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nat Immunol 2004; 5:272-9; PMID:14758359; http://dx.doi.org/10.1038/ni1039
69. Villalba M, Bi K, Rodriguez F, Tanaka Y, Schoenberger S, Altman A. Vav1/Rac-dependent actin cytoskeleton reorganization is required for lipid raft clustering in T cells. J Cell Biol 2001; 155:331-8; PMID:11684704; http://dx.doi.org/10.1083/jcb.200107080
70. Iwashima M. Kinetic perspectives of T cell antigen receptor signaling. A two-tier model for T cell full activation. Immunol Rev 2003; 191:196-210; PMID:12614361; http://dx.doi.org/10.1034/j.1600-065X.2003.00024.x
71. Guy CS, Vignali DA. Organization of proximal signal initiation at the TCR:CD3 complex. Immunol Rev 2009; 232:7-21; PMID:19909352; http://dx.doi.org/10.1111/j.1600-065X.2009.00843.x
72. Sanui T, Inayoshi A, Noda M, Iwata E, Oike M, Sasazuki T, Fukui Y. DOCK2 is essential for antigen-induced translocation of TCR and lipid rafts, but not PKC-theta and LFA-1, in T cells. Immunity 2003; 19:119-29; PMID:12871644; http://dx.doi.org/10.1016/S1074-7613(03)00169-9
73. Jacinto E, Werlen G, Karin M. Cooperation between Syk and Rac1 leads to synergistic JNK activation in T lymphocytes. Immunity 1998; 8:31-41; PMID:9462509; http://dx.doi.org/10.1016/S1074-7613(00)80456-2
74. Arrieumerlou C, Randriamampita C, Bismuth G, Trautmann A. Rac is involved in early TCR signaling. J Immunol 2000; 165:3182-9; PMID:10975833; http://dx.doi.org/10.4049/jimmunol.165.6.3182
75. Yu H, Leitenberg D, Li B, Flavell RA. Deficiency of small GTPase Rac2 affects T cell activation. J Exp Med 2001; 194:915-26; PMID:11581314; http://dx.doi.org/10.1084/jem.194.7.915
76. Chuang TH, Hahn KM, Lee JD, Danley DE, Bokoch GM. The small GTPase Cdc42 initiates an apoptotic signaling pathway in Jurkat T lymphocytes. Mol Biol Cell 1997; 8:1687-98; PMID:9307966; http://dx.doi.org/10.1091/mbc.8.9.1687
77. Chae HD, Lee KE, Williams DA, Gu Y. Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells. Blood 2008; 111:2597-605; PMID:18089848; http://dx.doi.org/10.1182/blood-2007-06-093237
78. Constant S, Pfeiffer C, Woodard A, Pasqualini T, Bottomly K. Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells. J Exp Med 1995; 182:1591-6; PMID:7595230; http://dx.doi.org/10.1084/jem.182.5.1591
79. Constant SL, Bottomly K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol 1997; 15:297-322; PMID:9143690; http://dx.doi.org/10.1146/annurev.immunol.15.1.297
80. Nakayama T, Yamashita M. The TCR-mediated signaling pathways that control the direction of helper T cell differentiation. Semin Immunol 2010; 22:303-9; PMID:20488727; http://dx.doi.org/10.1016/j.smim.2010.04.010
81. Sad S, Marcotte R, Mosmann TR. Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines. Immunity 1995; 2:271-9; PMID:7697544; http://dx.doi.org/10.1016/1074-7613(95)90051-9
82. Saxena A, Martin-Blondel G, Mars LT, Liblau RS. Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis. FEBS Lett 2011; 585:3758-63; PMID:21910991; http://dx.doi.org/10.1016/j.febslet.2011.08.047
83. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299:1057-61; PMID:12522256; http://dx.doi.org/10.1126/science.1079490
84. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005; 22:329-41; PMID:15780990; http://dx.doi.org/10.1016/j.immuni.2005.01.016
85. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 2010; 11:7-13; PMID:20016504; http://dx.doi.org/10.1038/ni.1818
86. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010; 10:490-500; PMID:20559327; http://dx.doi.org/10.1038/nri2785
87. Tanaka Y, So T, Lebedeva S, Croft M, Altman A. Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice. Blood 2005; 106:1286-95; PMID:15845902; http://dx.doi.org/10.1182/blood-2004-10-4074
88. Li B, Yu H, Zheng W, Voll R, Na S, Roberts AW, Williams DA, Davis RJ, Ghosh S, Flavell RA. Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science 2000; 288:2219-22; PMID:10864872; http://dx.doi.org/10.1126/science.288.5474.2219
89. Chemin K, Bohineust A, Dogniaux S, Tourret M, Guégan S, Miro F, Hivroz C. Cytokine secretion by CD4+ T cells at the immunological synapse requires Cdc42-dependent local actin remodeling but not microtubule organizing center polarity. J Immunol 2012; 189:2159-68; PMID:22821962; http://dx.doi.org/10.4049/jimmunol.1200156
90. Colacios C, Casemayou A, Dejean AS, Gaits-Iacovoni F, Pedros C, Bernard I, Lagrange D, Deckert M, Lamouroux L, Jagodic M, etal. The p. Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development. J Exp Med 2011; 208:2183-91; PMID:21948080; http://dx.doi.org/10.1084/jem.20102191
91. King C, Ilic A, Koelsch K, Sarvetnick N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 2004; 117:265-77; PMID:15084263; http://dx.doi.org/10.1016/S0092-8674(04)00335-6
92. Le Campion A, Gagnerault MC, Auffray C, Bécourt C, Poitrasson-Rivière M, Lallemand E, Bienvenu B, Martin B, Lepault F, Lucas B. Lymphopenia-induced spontaneous T-cell proliferation as a cofactor for autoimmune disease development. Blood 2009; 114:1784-93; PMID:19561321; http://dx.doi.org/10.1182/blood-2008-12-192120