ライフサイエンスコーパス: Aire

1 gulated in part by the autoimmune regulator (AIRE).

2 EC expressing the autoimmune regulator gene (Aire).

3 rtly controlled by the autoimmune regulator (Aire).

4 may partake in delivering inactive P-TEFb to Aire.

5 (high) mTECs expressing Tnfrsf11a, Ctss, and Aire.

6 ivation by release of stalled polymerases by Aire.

7 2(+) T cells was increased in humans lacking Aire.

8 are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance.

9 Here we showed that Autoimmune Regulator (Aire), a transcription coordinator involved in immune to

10 Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21,

11 We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly express

12 We show that Prdm1 acts independently of Aire, a crucial transcription factor implicated in medul

13 This analysis revealed initiation of Aire-activated genes to be comparable in Aire-deficient

14 ript mapping and ChIP-seq data indicate that Aire activates ectopic transcription not through specifi

15 sayed 26 thymoma samples for transcripts for AIRE and 16 peripheral tissue-specific autoantigens (TSA

16 Whereas relative transcript levels for AIRE and 7 of 16 TSAgs showed the expected underexpressi

17 eed, mice with a dominant-negative allele of Aire and deficiency in LYN spontaneously developed organ

18 provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in t

19 In mice lacking Aire and gammadelta T cells, certain tissues typically t

20 How AIRE and its partners mediate these various effects at t

21 ation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag gene

22 strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predispo

23 ered a previously unappreciated function for Aire and provide new insights into the biology of stem c

24 We found that Aire and some of its partners, notably those implicated

25 orrespondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain

26 uals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically

27 We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quan

28 lockade selectively and transiently depletes Aire and TSA expression in the thymus to create a window

29 Twelve missense or nonsense mutations in AIRE and two chimeric AIRE constructs were generated.

30 CD70 was expressed on Aire(-) and Aire(+) medullary thymic epithelial cells (m

31 to RANKL; and sustained expression of FoxN1, Aire, and tissue-restricted genes in CD80(hi) mTECs.

32 In patients with APECED, loss of AIRE appears to cause an autoimmune response against ent

33 expression of the transcriptional regulator Aire are involved in the regulation of thymus medullary

34 BioID analysis showed that AIRE associates with spindle-associated proteins in mES

35 sulin-variable number of tandem repeats) and AIRE (autoimmune regulator) have been associated with th

36 Aire:Brd4 association was critical for tolerance inducti

37 Aire:Brd4 binding depended on an orchestrated series of

38 ll, our results suggest that the presence of AIRE can trigger molecular events leading to an altered

39 Mutations in AIRE cause a monogenic autoimmune disease called autoimm

40 Mutations in AIRE cause a rare autosomal-recessive disease, autoimmun

41 copy analysis was performed for WT or mutant AIRE cellular localization.

42 nonsense mutations in AIRE and two chimeric AIRE constructs were generated.

43 Aire-containing complexes include 7SK RNA, the latter in

44 ng of super-enhancers to efficiently deliver Aire-containing complexes to local and distal transcript

45 lf commensal Ags in APECED and indicate that AIRE contributes to the regulation of gut homeostasis, a

46 nd trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found.

47 Aire controls immunologic tolerance by inducing a batter

48 The transcription factor Aire controls immunological tolerance by inducing the ec

49 AIRE decreases, via non-cell autonomous mechanisms, the

50 AIRE deficiency also affects B cell tolerance, but this

51 Together, our work showed how Aire deficiency can enhance immune responses against mel

52 In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TY

53 Aire deficiency in humans and mice manifests as spontane

54 Therefore, we hypothesized that Aire deficiency in mice may elevate immune responses to

55 Aire deficiency resulted in defective negative selection

56 suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechan

57 ins are autoantigens in humans and mice with AIRE deficiency.

58 clude known targets of autoimmunity in human AIRE deficiency.

59 efect of thymic presentation associated with AIRE-deficiency and raises novel questions what other fa

60 of Aire-activated genes to be comparable in Aire-deficient and wild-type MECs, but with a block to e

61 -methylation analysis of Aire-sufficient and Aire-deficient medullary epithelial cells (mTECs).

62 Aire-deficient mice displayed elevated T-cell immune res

63 We found that Aire-deficient mice had expanded thymic and peripheral p

64 he multiorgan autoimmunity characteristic of Aire-deficient mice.

65 and function modulate disease development in Aire-deficient mice.

66 of wild-type mice and expanded very early in Aire-deficient mice.

67 For example, AIRE-deficient patients are predisposed to vitiligo, an

68 autoantibodies, which are typically found in AIRE-deficient patients.

69 Furthermore, transplantation of Aire-deficient thymic stroma was sufficient to confer mo

70 ficient TSAg transcription in these aberrant AIRE-deficient tumors.

71 repertoires enriched in self-reactive cells (Aire-deficient) are transferred into cognate hosts.

72 tTreg development is predominantly AIRE dependent, with an AIRE-independent component.

73 MJ23 T(regs) underwent autoimmune regulator (Aire)-dependent thymic development in both male and fema

74 the commonalities and discrepancies between AIRE-dependent and -independent pGE, we analyzed the tra

75 We also found that AIRE-dependent and -independent TRA present several dist

76 Taken together, these results suggest that Aire-dependent central deletion and regulatory T cell-me

77 n Aire(+/+) mice, consistent with a role for Aire-dependent central deletion in establishing toleranc

78 Aire-dependent control of Il7 expression in mTECs regula

79 Approximately half of Aire-dependent deletion or Treg cell selection utilized

80 n structural alterations in conjunction with AIRE-dependent gene expression.

81 ire transactivation function, we screened an AIRE-dependent gene-expression system with a genome-scal

82 ty in a multiple sclerosis mouse model in an Aire-dependent manner.

83 We found that the impact of AIRE-dependent pGE is not limited to generation of TRA.

84 Aire-dependent processes are thought to promote both clo

85 us sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes.

86 We found that Aire-dependent thymic deletion of IRBP-specific T cells

87 athological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs,

88 re1 mTEC) and a decrease in the diversity of Aire-dependent tissue-restricted peripheral selfantigens

89 detect autoreactive T cells specific for the Aire-dependent tissue-specific antigen interphotorecepto

90 ulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

91 Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antige

92 Furthermore, we report that AIRE-dependent versus -independent TRA project nonredund

93 By tracking a clonal population of Aire-dependent, prostate-specific Treg cells in mice, we

94 deficient in the autoimmune regulatory gene Aire develop a spontaneous T-cell and macrophage-mediate

95 Both humans and mice lacking Aire develop multiorgan autoimmunity.

96 -specific HIPK2 deletion only mildly affects AIRE-directed pGE in vivo.

97 In mature medullary TEC, AIRE-driven pGE upregulates non-TRA coding genes that en

98 Expression of Aire during a perinatal age window is necessary and suff

99 Thus, Aire enforces immune tolerance by ensuring that distinct

100 Thus, Aire exerts multi-faceted autoimmune control that extend

101 Recently, extrathymic Aire-expressing cells (eTACs) have been described in mur

102 The origin and function of extrathymic Aire-expressing cells (eTACs) is incompletely defined.

103 , with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectabl

104 of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes

105 B-dependent development of normal numbers of AIRE-expressing mTECs in the complete absence of SP thym

106 Thus, therapies to deplete Aire-expressing mTECs represent an attractive strategy t

107 nd RANK-Ligand (RANKL) in the development of Aire-expressing mTECs.

108 be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells.

109 Remarkably, in mouse mTEC, Aire expression alone positively regulates 3980 tissue-r

110 Led by the observation that genes induced by Aire expression are generally characterized by a repress

111 single mTEC indicates that genes induced by Aire expression are transcribed stochastically at low ce

112 ty, the cis-regulatory elements that control Aire expression have remained obscure.

113 ogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tis

114 turn inhibits RANK signaling and facilitates AIRE expression in mTECs.

115 , we find that this element is essential for Aire expression in vivo and necessary to prevent spontan

116 JCI, Dragin and colleagues demonstrate that AIRE expression is downregulated in females as the resul

117 In mice and humans, thymic Aire expression is higher in males compared with females

118 We also demonstrated that AIRE expression is related to sexual hormones, as male c

119 he THP-1 human monocytic cell line, reducing AIRE expression resulted in significantly decreased TNF-

120 changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female

121 Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in D

122 Furthermore, when present, Aire expression-dependent transcript levels were 16-fold

123 noncoding DNA element that is essential for Aire expression.

124 icient mice did not show a sex disparity for AIRE expression.

125 taneously in NOD mice with a partial loss of Aire function (NOD.Aire(GW/+) mice) and is a T cell-medi

126 ymic deletion as a result of the hypomorphic Aire function and that these cells also escaped peripher

127 This study addresses the role of PHD2 in Aire function by comparing the behavior of wild-type and

128 e of central tolerance, and complete loss of AIRE function results in the development of autoimmune p

129 sight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-

130 In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune p

131 rgan autoimmunity syndrome that results from Aire gene mutations in humans.

132 Meyer et al. find that subjects lacking the AIRE gene, critical for self-tolerance in T lymphocytes,

133 , estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a th

134 utoimmune disease caused by mutations in the AIRE gene.

135 The autoimmune regulator (AIRE) gene contributes to the maintenance of central tol

136 The autoimmune regulator (AIRE) gene is crucial for establishing central immunolog

137 ial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by dr

138 ed by mutations in the autoimmune regulator (AIRE) gene, and myasthenia gravis (MG) with thymoma, sho

139 ed by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates th

140 ed by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of

141 ed by mutations of the autoimmune regulator (AIRE) gene.

142 ce with a partial loss of Aire function (NOD.Aire(GW/+) mice) and is a T cell-mediated disease.

143 cy accelerated neuropathy development in NOD.Aire(GW/+) mice, and Ab blockade of both B7-1 and B7-2 r

144 t of autoimmune peripheral neuropathy in NOD.Aire(GW/+) mice.

145 to ameliorate neuropathy development in NOD.Aire(GW/+) mice.

146 ophysiological evidence of neuropathy in NOD.Aire(GW/+) mice.

147 Interestingly, Aire has a highly tissue-restricted pattern of expressio

148 AIRE has been shown to promote DNA breaks via its intera

149 Using WT/mutant AIRE heterozygous forms to modulate the INS-VNTR target

150 on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to tar

151 Aire impacts immunological tolerance by regulating the e

152 ppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or trunc

153 o and suppressed the coactivator activity of AIRE in a kinase-dependent manner.

154 g the behavior of wild-type and PHD2-deleted Aire in both transfected cells and transgenic mice.

155 HIPK2 partially colocalized with AIRE in nuclear bodies upon cotransfection and in human

156 ire and the role of the autoimmune regulator Aire in thymic MPO expression, we compared the effects o

157 Moreover, HIPK2 phosphorylated AIRE in vitro and suppressed the coactivator activity of

158 role of Hipk2 in modulating the function of AIRE in vivo, we compared whole-genome gene signatures o

159 e transcription factor autoimmune regulator (Aire) in these processes.

160 XO3) (SKP1-CUL1-F box) complex ubiquitylates AIRE, increases its binding to the positive transcriptio

161 ent is predominantly AIRE dependent, with an AIRE-independent component.

162 distinct Treg populations are age-dependent, Aire-independent differences in the processing and prese

163 In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous and show greater

164 (lo) mTEC subset and preferentially included AIRE-independent TRAs.

165 ) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the eme

166 TECs and CD8alpha(+) DCs for presentation of Aire-induced self-antigens to developing thymocytes.

167 In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous

168 the effect of the splicing factor Hnrnpl on Aire-induced transcription.

169 Aire induces the expression of a large set of autoantige

170 ast two-hybrid screen, we searched for novel AIRE-interacting proteins and identified the homeodomain

171 Here we identified two Aire-interacting proteins known to be involved in gene r

172 Aire is a transcription factor that controls T cell tole

173 Aire is an important regulator of immunological toleranc

174 to analyze whether each functional domain of AIRE is critical for the activation of INS-VNTR in human

175 Thymopoiesis in the absence of AIRE is implicated in both syndromes.

176 We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to au

177 AIRE is modified post-translationally by phosphorylation

178 AIRE is part of higher-order multiprotein complexes, whi

179 n AIH on a BALB/c mouse background, in which Aire is truncated at exon 2.

180 The autoimmune regulator (AIRE) is a transcription factor which is expressed in me

181 The autoimmune regulator (Aire) is essential for prevention of autoimmunity; its r

182 The autoimmune regulator (AIRE) is to date the only validated molecule known to re

183 mus, driven in part by autoimmune regulator (Aire), is critical for the protection of peripheral tiss

184 nd mononuclear infiltration of the retina in Aire knockout (KO) mice triggers the onset of uveitis fr

185 the three main TEC subsets in wild-type and Aire knockout mice.

186 nt of exocrine and ocular surface disease in Aire knockout mice.

187 Using the Aire KO mouse model, we demonstrated an essential role f

188 , certain tissues typically targeted in the "Aire-less" disease, notably the retina, were only minima

189 AIRE levels in human thymus grafted in immunodeficient m

190 strate that disease-causing mutations in the AIRE locus are more common than previously appreciated a

191 ssociation between estrogen and reduction of AIRE may at least partially account for the elevated inc

192 hin the NOD Ica1 core promoter may determine AIRE-mediated down-regulation of ICA69 expression in med

193 to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thy

194 Thus, Aire-mediated expression of peripheral tissue antigens d

195 indings provide a mechanism by which loss of AIRE-mediated immune tolerance leads to intestinal disor

196 Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoim

197 Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender

198 AIRE-mediated transcription was not only enhanced by TOP

199 A model antigen specifically expressed in Aire(+) medullary TECs (mTECs) induced efficient deletio

200 CD70 was expressed on Aire(-) and Aire(+) medullary thymic epithelial cells (mTECs) and on

201 in self-Ag-presenting, autoimmune regulator (AIRE)(+) medullary thymic epithelial cells (mTECs).

202 The high rate of apoptosis in pre-Aire MHCII(lo) mTECs points to a "quality control" step

203 henotypically overlapping pre- from the post-Aire MHCII(lo) stage has been lacking.

204 ed to include a third stage, namely the post-Aire MHCII(lo) subset as identified by lineage-tracing m

205 -/-) mice had more severe renal disease than Aire(+/+) mice, consistent with a role for Aire-dependen

206 IRBP tetramers in Aire(-/-) mice, but not in Aire(+/+) mice.

207 entially expressed by Foxp3(+) Treg cells in Aire(+/+) mice.

208 We used Aire(-/-) mice as a model of APECED, and studied the eff

209 Aire(-/-) mice developed defensin-specific T cells that

210 Aire(-/-) mice developed defensin-specific T cells.

211 Immunized Mpo(-/-) and Aire(-/-) mice developed significantly more proinflammat

212 anti-glomerular basement membrane antibody, Aire(-/-) mice had more severe renal disease than Aire(+

213 emonstrating defective T cell development in Aire(-/-) mice is not because of a loss of CCR4-mediated

214 Here, examination of autoimmune lesions in Aire(-/-) mice revealed an unexpected third possibility.

215 red the effects of immunizing Mpo(-/-) mice, Aire(-/-) mice, and control littermates with MPO.

216 T cells specific for both IRBP tetramers in Aire(-/-) mice, but not in Aire(+/+) mice.

217 The induction of Aire mRNA in keratinocytes depends on a functional inter

218 AIRE mRNA levels were elevated in thymic tissue from DS

219 man and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty.

220 er, by mapping OPG expression to a subset of Aire(+) mTEC, our data show how cis- and trans-acting me

221 tal repertoire secondary to a decline in the Aire(+)mTEC(high) cell pool.

222 HD interfered with the capacity of recipient Aire(+)mTEC(high) to sustain TRA diversity.

223 growth factor-7, maintained a stable pool of Aire(+)mTEC(high), with an improved TRA transcriptome de

224 In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-

225 athways are essential for differentiation of AIRE(+) mTECs.

226 on of CD80(lo), Aire(-) mTECs into CD80(hi), Aire(+) mTECs; responsiveness to RANKL; and sustained ex

227 on and terminal differentiation of CD80(lo), Aire(-) mTECs into CD80(hi), Aire(+) mTECs; responsivene

228 nt-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity.

229 This study supports the notion that AIRE mutation could specifically affect human insulin ge

230 systemic autoimmunity, could combine with an Aire mutation to provoke organ-specific autoimmunity.

231 ent of AIH in APS-1 is dependent on specific Aire mutations and genetic background genes.

232 ease manifestation was dependent on specific Aire mutations and the genetic background of the mice.

233 l. discovered heterozygous dominant-negative AIRE mutations in patients with certain forms of autoimm

234 We found that all of the AIRE mutations resulted in loss of transcriptional activ

235 ave described a variety of dominant-negative AIRE mutations that likely contribute to human autoimmun

236 erstand fertility defects in humans carrying Aire mutations.

237 AIRE nuclear localization in the human thymic epithelial

238 To study the influence of Aire on thymic selection in a physiological setting, we

239 lso identified topoisomerase 1 as a cardinal Aire partner that colocalized on super-enhancers and was

240 Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease wit

241 ntly, there are few molecular details on how Aire performs this crucial function.

242 The autoimmune regulator (Aire) plays a critical role in central tolerance by prom

243 The autoimmune regulator (Aire) plays a critical role in central tolerance by prom

244 r both T-cell and B-cell areas, distant from Aire(pos) and CD11c(pos) cells.

245 DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-posit

246 Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen ex

247 c transcription factor autoimmune regulator (Aire) prevents autoimmunity in part by promoting express

248 Androgen recruits AR to Aire promoter regions, with consequent enhancement of Ai

249 ed the number of methylated CpG sites in the AIRE promoter.

250 sult of estrogen-mediated alterations at the AIRE promoter.

251 We report that Aire promotes the perinatal generation of a distinct com

252 Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes

253 The autoimmune regulator (AIRE) protein is the key factor in thymic negative selec

254 tion, facilitated by decreased expression of Aire rather than impaired regulatory T cell generation,

255 -state postnatal thymus TPA(lo)MHCII(lo) pre-Aire rather than terminally differentiated post-Aire TPA

256 protein zero, an Ag for which expression is Aire-regulated in the thymus.

257 Although Aire regulates expression of the CCR4 ligands CCL17 and

258 th this, mTECs continue to express Fezf2 and Aire, regulators of intrathymic self-antigens, and suppo

259 his interaction ensures proper expression of AIRE-responsive tissue-specific antigens in the thymus.

260 es of posttranslational modifications within Aire's caspase activation and recruitment domain.

261 We explored Aire's collaboration with the bromodomain-containing pro

262 ternal and zygotic knockout further revealed Aire's critical functions for spindle assembly in preimp

263 Aire's functional allies were validated on transfected a

264 ng TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex

265 terminal LESLL motif as a critical motif for AIRE's mitotic function.

266 RNA processing; it also was not required for Aire's nuclear translocation or regional distribution.

267 Aire's primary mechanism of action is to regulate transc

268 or tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes.

269 To better understand Aire's specificity, we performed single-cell RNA-seq and

270 Each of Aire's target genes was induced in only a minority of mT

271 ion, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs.

272 Thus, Aire's two PHDs seem to play distinct roles in the scena

273 llele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three

274 cell RNA-seq and DNA-methylation analysis of Aire-sufficient and Aire-deficient medullary epithelial

275 elongation after 50-100 bp in the absence of Aire, suggesting activation by release of stalled polyme

276 and the exchange of histone H1 with HMGB1 at AIRE target gene promoters.

277 s two plant homeodomains (PHDs), PHD1, helps Aire target poorly transcribed loci by "reading" the met

278 Our findings are consistent with AIRE targeting and inducing the promiscuous expression o

279 irst plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically chara

280 ined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many sel

281 cells, independently of their dependence on Aire, therefore indicating a general effect of Hnrnpl on

282 exual hormones, as male castration decreased AIRE thymic expression and estrogen receptor alpha-defic

283 PHD2 was required for Aire to interact with sets of protein partners involved

284 PHD2 strongly influenced the ability of Aire to regulate the medullary epithelial cell transcrip

285 that mRNA processing factors cooperate with Aire to release stalled polymerases and to activate ecto

286 e transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance.

287 e rather than terminally differentiated post-Aire TPA(hi)MHCII(lo) mTECs were marked for apoptosis at

288 ctrum of molecular mechanisms underlying the Aire transactivation function, we screened an AIRE-depen

289 oter regions, with consequent enhancement of Aire transcription.

290 ator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown.

291 More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expre

292 Loss of function analysis revealed that Aire was important for centrosome number regulation and

293 e reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several

294 SAs largely depends on autoimmune regulator (Aire), which is expressed in mature mTECs.

295 Aire, which induces tissue-specific antigen expression i

296 AIRE, which is phosphorylated on two specific residues n

297 ugh the activity of the autoimmune regulator AIRE, which promotes central T cell tolerance.

298 ed by mutations in the autoimmune regulator (AIRE, which regulates immune tolerance) that allow self-

299 immune rejection of melanoma in an otherwise Aire wild-type host.

300 cers and was required for the interaction of Aire with all of its other associates.