ライフサイエンスコーパス: mTEC

1 mTECs also express multiple transcription factors requir

2 mTECs regulate T cell tolerance by ectopically expressin

3 ted reciprocal link between DETC and Aire(+) mTEC maturation.

4 ure thymocytes are not essential for Aire(+) mTEC development, use of an inducible ZAP70 transgenic m

5 Despite this role, the mechanisms of Aire(+) mTEC development remain unclear, particularly those stag

6 apping OPG expression to a subset of Aire(+) mTEC, our data show how cis- and trans-acting mechanisms

7 Aire(-) mTEC progenitors into CD80(+)Aire(+) mTECs, and that transplantation of RANK-deficient thymic

8 80(lo), Aire(-) mTECs into CD80(hi), Aire(+) mTECs; responsiveness to RANKL; and sustained expression

9 hanisms leading to the generation of Aire(+) mTECs and highlight a previously unrecognized role for C

10 at emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to alphabet

11 nally, although initial formation of Aire(+) mTECs depends upon RANK signaling, continued mTEC develo

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

13 are essential for differentiation of AIRE(+) mTECs.

14 orally linked with the appearance of Aire(+) mTECs.

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

16 rfered with the capacity of recipient Aire(+)mTEC(high) to sustain TRA diversity.

17 ertoire secondary to a decline in the Aire(+)mTEC(high) cell pool.

18 maturation of RANK-expressing CD80(-)Aire(-) mTEC progenitors into CD80(+)Aire(+) mTECs, and that tra

19 erminal differentiation of CD80(lo), Aire(-) mTECs into CD80(hi), Aire(+) mTECs; responsiveness to RA

20 ing medullary thymic epithelial cells (Aire1 mTEC) and a decrease in the diversity of Aire-dependent

21 programs of epithelial differentiation among mTECs.

22 ion, maintenance of thymic architecture, and mTEC differentiation.

23 ets that reside within both the mTEC(hi) and mTEC(lo) compartments and that represent direct targets

24 edullary thymic epithelial cells (mTEC), and mTEC development in turn requires signals from mature si

25 tively than adult TECs; 2) whereas cTECs and mTECs had similar turnover rates in young mice, the turn

26 both cortical and medullary TECs (cTECs and mTECs) proliferated more actively in females than males.

27 the relationship between Il7(YFP+) TECs and mTECs.

28 ency of Il7(YFP+) TECs gradually declines as mTEC development unfolds, we explored the relationship b

29 I(lo) subset (<20%) potentially qualified as mTEC precursors.

30 fore, while protecting against autoimmunity, mTECs simultaneously limit the generation of tumor-speci

31 reveal an unappreciated cooperation between mTECs and CD8alpha(+) DCs for presentation of Aire-induc

32 pha transgene also rescues the UEA-1 binding mTEC subset even though K5 expression is not detectable

33 Development of both mTEC subsets requires activation of the noncanonical NF-

34 oxN1 is required for the development of both mTECs and cTECs in thymic organogenesis, it is most impo

35 CD70 on both mTECs and DCs contributed to Treg cell development as sh

36 presentation of endogenous self-antigens by mTECs.

37 en this autophagy substrate was expressed by mTECs in high amounts, endogenous presentation and indir

38 lineages and that expression of some TRAs by mTECs may reflect this activity.

39 Thus, expression of some TRAs by mTECs may represent coordinated gene expression that ref

40 f peripheral tissue-restricted Ags (TRAs) by mTECs remain poorly defined.

41 F-kappaB-mediated differentiation of CD80(+) mTECs.

42 ll, Il7(YFP+) TECs can generate some CD80(+) mTECs in a stepwise differentiation process via YFP(-)Ly

43 sed primary murine tracheal epithelial cell (mTEC) cultures to investigate antiviral and cytokine res

44 show that medullary thymic epithelial cell (mTEC) development involves hemopoietic cross-talk, and n

45 regulating medullary thymic epithelial cell (mTEC) development.

46 del of the medullary thymic epithelial cell (mTEC) lineage from immature MHC class II (MHCII)(lo) to

47 stimulate medullary thymic epithelial cell (mTEC) maturation are partially elucidated, the signals t

48 t contains medullary thymic epithelial cell (mTEC) networks to support negative selection and Foxp3(+

49 (cTEC) and medullary thymic epithelial cell (mTEC) subsets take place.

50 at mature medullary thymic epithelial cells (mTEC(high)) expressing the autoimmune regulator are targ

51 in mature medullary thymic epithelial cells (mTEC(high)) partly controlled by the autoimmune regulato

52 generate medullary thymic epithelial cells (mTEC) from their immature progenitors, we describe work

53 e thymus, medullary thymic epithelial cells (mTEC) regulate T cell tolerance via negative selection a

54 endent on medullary thymic epithelial cells (mTEC), and mTEC development in turn requires signals fro

55 d Aire(+) medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medull

56 in mouse medullary thymic epithelial cells (mTECs) and peripheral lymphoid stromal cells, which have

57 genes in medullary thymic epithelial cells (mTECs) and, consequently, negative selection of effector

58 Medullary thymic epithelial cells (mTECs) are critical in establishing and maintaining the

59 role for medullary thymic epithelial cells (mTECs) during iNKT cell development in the mouse thymus.

60 xpressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both n

61 Medullary thymic epithelial cells (mTECs) eliminate self-reactive T cells by displaying a d

62 Medullary thymic epithelial cells (mTECs) express a broad spectrum of tissue- restricted se

63 ed Ags by medullary thymic epithelial cells (mTECs) is associated with negative selection.

64 (TRAs) in medullary thymic epithelial cells (mTECs) is essential for the induction of self-tolerance

65 (TRAs) in medullary thymic epithelial cells (mTECs) is essential to safeguard self-tolerance.

66 APCs and medullary thymic epithelial cells (mTECs) on the conventional and Treg TCR repertoire, as w

67 xpressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by exp

68 Medullary thymic epithelial cells (mTECs) play an essential role in establishing central to

69 Medullary thymic epithelial cells (mTECs) play an important role in T cell tolerance and pr

70 APCs and medullary thymic epithelial cells (mTECs) played nonoverlapping roles in shaping the T cell

71 (TRAs) by medullary thymic epithelial cells (mTECs) plays an essential role in T cell tolerance.

72 xpressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that,

73 In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an es

74 s involve medullary thymic epithelial cells (mTECs), which use endogenously expressed peripheral-tiss

75 epends on medullary thymic epithelial cells (mTECs), whose development, in turn, requires signals fro

76 xpressing medullary thymic epithelial cells (mTECs), without affecting its expression in the beta-cel

77 cells and medullary thymic epithelial cells (mTECs)--are yet to be developed.

78 (AIRE)(+) medullary thymic epithelial cells (mTECs).

79 dependent medullary thymic epithelial cells (mTECs).

80 d Aire-deficient medullary epithelial cells (mTECs).

81 mTECs depends upon RANK signaling, continued mTEC development to the involucrin(+) stage maps to acti

82 , their impact on the mechanisms controlling mTEC homeostasis is poorly understood, as are the proces

83 in nude mice, and associated with defective mTEC-mediated elimination of thymocytes in a T cell rece

84 esignated as ID-TEC mice for insulin-deleted mTEC) developed diabetes spontaneously around 3 weeks af

85 developmental programs active in developing mTECs-may be equally plausible.

86 alized property of terminally differentiated mTECs.

87 a key property of terminally differentiated mTECs.

88 A distinct mTEC subset binds UEA-1 and expresses K8, but not K5 or

89 nts to a "quality control" step during early mTEC differentiation.

90 transcriptome of medullary thymic epithelia (mTECs) to produce a stroma decorated with peripheral sel

91 tly transfected medullary thymus epithelial (mTEC(+)) and B-cell (M12)-derived cell lines.

92 , the extent of medullary thymic epithelium (mTEC) heterogeneity, and the mechanisms that mediate the

93 lopment of normal numbers of AIRE-expressing mTECs in the complete absence of SP thymocytes.

94 Thus, therapies to deplete Aire-expressing mTECs represent an attractive strategy to increase the p

95 RANKL) in the development of Aire-expressing mTECs.

96 gnaling pathway selectively in K5-expressing mTECs and 2) the K5-expressing subset either contains im

97 nate immune cell system drives initial fetal mTEC development via expression of RANKL, but not CD40L.

98 with each TRA being expressed in only a few mTECs.

99 or of NF-kappaB (RANK), which is central for mTEC differentiation, deficiency of p53 in TECs altered

100 and CD40, which are otherwise necessary for mTEC development, but is not sufficient to overcome the

101 This requirement for mTECs correlates with their expression of genes required

102 the TCR repertoire in a manner distinct from mTEC presentation.

103 Furthermore, mTEC development is abnormal in iNKT cell-deficient mice

104 ire, and tissue-restricted genes in CD80(hi) mTECs.

105 MHC class II (MHCII)(lo) to mature MHCII(hi) mTECs has recently been extended to include a third stag

106 Prss16 and segregates from CD80(+)CD40(high) mTECs expressing Tnfrsf11a, Ctss, and Aire.

107 lear bodies upon cotransfection and in human mTECs in situ.

108 Here, we show that subsets of human mTECs expressing a particular TRA coexpress distinct set

109 TPA also further subdivided human mTECs, although with different subset distribution.

110 e needed to overcome TRAF3-imposed arrest in mTEC development mediated by inhibition of nonclassical

111 rWSN NS1 R38A replication is attenuated in mTEC cultures; however, viral antigen is detected predom

112 A decline in mTEC(high) cell pool size, which purges individual tissu

113 , p53cKO mice presented premature defects in mTEC-dependent regulatory T-cell differentiation and thy

114 CD40-CD40L results in profound deficiency in mTEC development comparable to that observed in the abse

115 (m) and cortical TEC, further elaborated in mTEC, and completed in mature mTEC expressing the autoim

116 of impaired thymic ectopic OVA expression in mTEC(high) cells.

117 inally, we show that whereas the increase in mTEC availability in OPG-deficient (Tnfrsf11b(-/-)) mice

118 olecular components and pathways involved in mTEC differentiation in general and in promiscuous gene

119 e strongly associated with H3K27me3 marks in mTEC.

120 dence for a stepwise involvement of TNFRs in mTEC development, with CD40 upregulation induced by init

121 The failure to properly express CII in mTECs of Lta(-/-) and Ltbr(-/-) mice leads to overt auto

122 opic expression of type II collagen (CII) in mTECs and the corresponding central tolerance to CII are

123 /-) mice results in a profound deficiency in mTECs.

124 us, although it modulates gene expression in mTECs and in addition affects the size of the medullary

125 Our findings characterize TRA expression in mTECs as a coordinated process that might involve local

126 Aire-dependent control of Il7 expression in mTECs regulated the size of thymic IL-17A(+)Vgamma6(+)Vd

127 further that depletion of Ins2 expression in mTECs was sufficient to break central tolerance and indu

128 nduces tissue-specific antigen expression in mTECs, affected the TCR repertoire in a manner distinct

129 signaling and facilitates AIRE expression in mTECs.

130 ment of enhancer-associated histone marks in mTECs and also has characteristics of being an NF-kappaB

131 found that humans also lacked alpha-MyHC in mTECs and had high frequencies of alpha-MyHC-specific T

132 ressed in the thymic stroma, specifically in mTECs.

133 itial and terminal differentiation stages in mTECs.

134 Cs are highly heterogeneous; each individual mTEC expresses a limited spectrum of TRAs, and the frequ

135 imarily cytoplasmic localization in infected mTEC cultures.

136 p3(+) thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3(+) nTreg ce

137 nstrates that the emergence of involucrin(+) mTECs critically depends upon the presence of mature sin

138 rmal equivalent, for the culture of isolated mTECs.

139 en by a K5 promoter restores the K5(+)K14(+) mTEC subset in IKKalpha(-/-) mice.

140 xpressed genes were confined to the CD80(lo) mTEC subset and preferentially included AIRE-independent

141 high rate of apoptosis in pre-Aire MHCII(lo) mTECs points to a "quality control" step during early mT

142 ly differentiated post-Aire TPA(hi)MHCII(lo) mTECs were marked for apoptosis at an exceptionally high

143 elaborated in mTEC, and completed in mature mTEC expressing the autoimmune regulator gene (Aire).

144 ive differentiation stages within the mature mTEC subset and, in vitro, interconverted along this seq

145 y architecture and fewer functionally mature mTECs under steady-state conditions.

146 ed with activation of the p53 gene in mature mTECs.

147 gulator (Aire), which is expressed in mature mTECs.

148 ptor activator for NF-kappaB ligand-mediated mTEC development.

149 ms operate independently of LTbetaR-mediated mTEC development and organization.

150 hat a functional compromise of the medullary mTEC(high) compartment may link alloimmunity to the deve

151 e to cells of cortical (cTEC) and medullary (mTEC) phenotypes, via compartment-specific progenitors.

152 oter-driven somatic epithelial cells (mostly mTECs and possibly some adult epithelial stem cells) was

153 Remarkably, in mouse mTEC, Aire expression alone positively regulates 3980 ti

154 the thymus medulla by operating on multiple mTEC targets.

155 s study, we have investigated the control of mTEC homeostasis and examined how this process impacts t

156 mpose important constraints for any model of mTEC differentiation and function.

157 Cytokine pretreatment of mTEC cultures and Vero cells suggest that rWSN NS1 R38A

158 They also suggest a stepwise process of mTEC development, in which RANK is a master player in co

159 edulla to support the balanced production of mTEC-dependent Foxp3(+) Treg.

160 p53 controls specific and broad programs of mTEC differentiation.

161 TRAF3 plays a central role in regulation of mTEC development by imposing requirements for SP T cells

162 results identify Sin as a novel regulator of mTEC development and T cell tolerance, and suggest that

163 urnover, differentiation, and replacement of mTEC populations in the adult thymus.

164 r data, we derived the following sequence of mTEC differentiation: TPA(lo)MHCII(lo) --> TPA(lo)MHCII(

165 ch self-antigen is expressed only in 1-3% of mTECs).

166 pathway, have an almost complete absence of mTECs, with resulting autoimmune pathology.

167 tore iNKT cell development in the absence of mTECs.

168 as a pathway important in the development of mTECs, because mice lacking RelB, NIK, or IKKalpha, crit

169 findings suggest that the differentiation of mTECs can involve some of the developmental programs use

170 y, Sin deficiency inhibited the expansion of mTECs in response to in vivo administration of keratinoc

171 -dimensional model preserves key features of mTECs: proliferation and terminal differentiation of CD8

172 mited spectrum of TRAs, and the frequency of mTECs that express any individual TRA is quite low (>0.4

173 it is most important for the maintenance of mTECs in the postnatal thymus, which are in turn necessa

174 that direct proliferation and maturation of mTECs are provided by members of the tumor necrosis fact

175 rget genes was induced in only a minority of mTECs, independently of DNA-methylation patterns, as sma

176 ters activated in concert in a proportion of mTECs.

177 n patterns, each present in only a subset of mTECs.

178 urnover rates in young mice, the turnover of mTECs was more rapid than that of cTECs in adults; and 3

179 One mTEC subset expresses keratin 5 (K5) and K14, but fails

180 -restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (

181 red whole-genome gene signatures of purified mTEC subsets from TEC-specific Hipk2 knockout mice with

182 how multiple hemopoietic cell types regulate mTEC development through differential provision of RANKL

183 hat occur post-Aire expression and represent mTEC terminal differentiation.

184 mparison of the transcriptomes of 174 single mTEC indicates that genes induced by Aire expression are

185 How this process is regulated in single mTECs and is coordinated at the population level, such t

186 Our data suggest that single mTECs shift through distinct gene pools, thus scanning a

187 sion in individual and small pools of sorted mTECs show that mTECs are highly heterogeneous; each ind

188 tudy, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requireme

189 ily disrupts the integrity of medullary TEC (mTEC) niche, a defect that spreads to the adult cortical

190 fically expressed in Aire(+) medullary TECs (mTECs) induced efficient deletion via direct presentatio

191 more severe deterioration in medullary TECs (mTECs) than in cortical TECs (cTECs).

192 d map emphazises close parallels of terminal mTEC development with that of skin, undergoing an altern

193 In this study, we show that mTEC development is severely impaired and autoimmune man

194 within the thymus medulla, and it shows that mTEC homeostasis is not a rate-limiting step in intrathy

195 We report here that mTECs from adult mice are mitotically active, implying c

196 These data indicate that mTECs exert a cell-autonomous role in central T cell tol

197 al and small pools of sorted mTECs show that mTECs are highly heterogeneous; each individual mTEC exp

198 Our data suggest that mTECs and DCs form dedicated niches in the thymic medull

199 The mTEC population in adult thymus expresses transcription

200 RANK(+) subsets that reside within both the mTEC(hi) and mTEC(lo) compartments and that represent di

201 l (Treg) development, and alterations in the mTEC compartment can lead to tolerance breakdown and aut

202 r, on average, in individual TEC than in the mTEC population.

203 rmacological means increased the size of the mTEC compartment, enhanced negative selection and functi

204 l mimicking the developmental biology of the mTEC lineage has hampered the molecular analysis of the

205 have defined several basic properties of the mTEC population that refine our understanding of these c

206 s altered multiple functional modules of the mTEC transcriptome, including tissue-restricted antigen

207 quently controlling proliferation within the mTEC compartment.

208 sion and terminal differentiation within the mTEC lineage are temporally separable events that are co

209 Consistent with this, mTECs continue to express Fezf2 and Aire, regulators of

210 inism but is 'bookmarked' and stable through mTEC divisions, which ensures more effective presentatio

211 Thus, mTEC development can occur in the absence of cross-talk

212 node stromal cells are functionally akin to mTECs and provide a direct strategy for purging the peri

213 Here we show that mice with mTEC depletion due to conditional deletion of Traf6 expr

214 CD4(+)3(-) cells are closely associated with mTECs in adult thymus, and in fetal thymus their appeara

215 ell development is medullary dependent, with mTECs fostering the generation of Foxp3(-)CD25(+) nTreg