Coordinating Development of Medullary Thymic Epithelial Cells
2008; Cell Press; Volume: 29; Issue: 3 Linguagem: Inglês
10.1016/j.immuni.2008.09.001
ISSN1097-4180
Autores Tópico(s)Immune Cell Function and Interaction
ResumoThree papers in this issue of Immunity (Akiyama et al., 2008Akiyama T. Shimo Y. Yanai H. Qin J. Ohshima D. Maruyama Y. Asaumi Y. Kitazawa J. Takayanagi H. Penninger J.M. et al.Immunity. 2008; 29 (this issue): 423-437Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar, Hikosaka et al., 2008Hikosaka Y. Nitta T. Ohigashi I. Yano K. Ishimaru N. Hayashi Y. Matsumoto M. Matsuo K. Penninger J.M. Takayanagi H. et al.Immunity. 2008; 29 (this issue): 438-450Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, Irla et al., 2008Irla M. Hugues S. Gill J. Nitta T. Hikosaka Y. Williams I.R. Hubert F.-X. Scott H.S. Takahama Y. Holländer G.A. Reith W. Immunity. 2008; 29 (this issue): 451-463Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar) together reveal coordinating roles for autoreactive T cells and TNF receptor superfamily members in the development of medullary thymic epithelial cells. Three papers in this issue of Immunity (Akiyama et al., 2008Akiyama T. Shimo Y. Yanai H. Qin J. Ohshima D. Maruyama Y. Asaumi Y. Kitazawa J. Takayanagi H. Penninger J.M. et al.Immunity. 2008; 29 (this issue): 423-437Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar, Hikosaka et al., 2008Hikosaka Y. Nitta T. Ohigashi I. Yano K. Ishimaru N. Hayashi Y. Matsumoto M. Matsuo K. Penninger J.M. Takayanagi H. et al.Immunity. 2008; 29 (this issue): 438-450Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, Irla et al., 2008Irla M. Hugues S. Gill J. Nitta T. Hikosaka Y. Williams I.R. Hubert F.-X. Scott H.S. Takahama Y. Holländer G.A. Reith W. Immunity. 2008; 29 (this issue): 451-463Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar) together reveal coordinating roles for autoreactive T cells and TNF receptor superfamily members in the development of medullary thymic epithelial cells. The crucial role of medullary thymic epithelial cells (mTECs) in establishing peripheral organ-specific central tolerance has now been well accepted. This is attributed to two breakthrough findings: (1) the discovery of tissue-restricted self-antigen (TRA) expression in medullary thymic epithelial cells (mTECs) (Kyewski and Klein, 2006Kyewski B. Klein L. Annu. Rev. Immunol. 2006; 24: 571-606Crossref PubMed Scopus (554) Google Scholar); and (2) the identification of the gene encoding autoimmune regulator (AIRE) as a master controller for a large portion of TRAs (Anderson et al., 2002Anderson M.S. Venanzi E.S. Klein L. Chen Z. Berzins S.P. Turley S.J. von Boehmer H. Bronson R. Dierich A. Benoist C. Mathis D. Science. 2002; 298: 1395-1401Crossref PubMed Scopus (1757) Google Scholar). Since these findings, the study of development of mTECs and regulation of TRAs in mTECs has been the spotlight in the field of research of organ-specific central tolerance. During thymus development, bipotent TEC progenitors, which are present at least until the neonatal stage, differentiate into cortical and medullary TEC progenitors (Anderson et al., 2007Anderson G. Lane P.J.L. Jenkinson E.J. Nat. Rev. Immunol. 2007; 7: 954-963Crossref PubMed Scopus (150) Google Scholar). The CD80−Aire− mTEC progenitors then undergo a stepwise differentiation to generate immature MHCIIloCD80loAire− mTECs and then mature MHCIIhiCD80hi Aire+ mTECs. The cellular and molecular mechanisms underlying the development of mTECs are not well understood. Three studies (Akiyama et al., 2008Akiyama T. Shimo Y. Yanai H. Qin J. Ohshima D. Maruyama Y. Asaumi Y. Kitazawa J. Takayanagi H. Penninger J.M. et al.Immunity. 2008; 29 (this issue): 423-437Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar, Hikosaka et al., 2008Hikosaka Y. Nitta T. Ohigashi I. Yano K. Ishimaru N. Hayashi Y. Matsumoto M. Matsuo K. Penninger J.M. Takayanagi H. et al.Immunity. 2008; 29 (this issue): 438-450Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, Irla et al., 2008Irla M. Hugues S. Gill J. Nitta T. Hikosaka Y. Williams I.R. Hubert F.-X. Scott H.S. Takahama Y. Holländer G.A. Reith W. Immunity. 2008; 29 (this issue): 451-463Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar) in this issue of Immunity have helped to address some of the basic questions and depict a more detailed picture about mTEC development. At the intracellular level, studies of gene-deficient and mutant mice have strongly and clearly suggested that both classical and alternative NF-κB pathways, as revealed in Traf6−/−, aly/aly, Relb−/−, and Nfkb2−/− mice, are involved in the development of mTECs (Akiyama et al., 2008Akiyama T. Shimo Y. Yanai H. Qin J. Ohshima D. Maruyama Y. Asaumi Y. Kitazawa J. Takayanagi H. Penninger J.M. et al.Immunity. 2008; 29 (this issue): 423-437Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar, Zhu et al., 2006Zhu M. Chin R.K. Fu Y.X. J. Clin. Invest. 2006; 116: 2964-2971Crossref PubMed Scopus (99) Google Scholar). Traf6−/−, aly/aly, and Relb−/− strains of mice almost completely lack of UEA-1+ mTECs. Regarding events at the cell surface, however, understanding of mTEC development has been a lot more obscure. Although several tumor necrosis factor receptor superfamily (TNFRSF) members (e.g., LTβR, RANK, and CD40) have been indicated in mTEC development, the mild or partial effect revealed in each single-deficient mice hampers a clear understanding of their individual roles (Akiyama et al., 2008Akiyama T. Shimo Y. Yanai H. Qin J. Ohshima D. Maruyama Y. Asaumi Y. Kitazawa J. Takayanagi H. Penninger J.M. et al.Immunity. 2008; 29 (this issue): 423-437Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar, Boehm et al., 2003Boehm T. Scheu S. Pfeffer K. Bleul C.C. J. Exp. Med. 2003; 198: 757-769Crossref PubMed Scopus (293) Google Scholar, Chin et al., 2003Chin R.K. Lo J.C. Fu Y.X. Nat. Immun. 2003; 4: 1121-1127Crossref Scopus (172) Google Scholar). These observations suggest redundant and/or cooperative roles of these receptors in mTEC development. In one report in this issue, Akiyama et al., 2008Akiyama T. Shimo Y. Yanai H. Qin J. Ohshima D. Maruyama Y. Asaumi Y. Kitazawa J. Takayanagi H. Penninger J.M. et al.Immunity. 2008; 29 (this issue): 423-437Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar have proven a cooperative role of RANKL-RANK and CD40L-CD40 for the development of mTECs by analyzing Tnfrsf11a−/−, CD40−/−, and Tfnrsf11a−/−CD40−/− thymi. First, comparison of Tnfrsf11a−/− and CD40−/− thymi shows that RANK signal plays a dominant role in mTECs development. Second, flow cytometry analysis reveals that RANKL preferentially regulates the development of the mature mTEC subset (MHCIIhi) whereas CD40L is rather preferentially involved in the development of immature mTEC subset (MHCIIlo). Third, the RANK signal is essential for the development of mTECs at the embryo stage whereas the effect of CD40 signal doesn't show up until postnatal day 3. However, RANK and CD40 signals might also have redundant function. This was suggested by data that either RANKL or CD40L is sufficient for inducing mature mTEC development and the expression of Aire and TRAs in fetal thymic organ culture (FTOC). Therefore, this study suggests that RANK and CD40 signals have partially distinct functions in mTEC development. A possible caveat of this study might be the influence of the severe peripheral autoimmune phenotype on the development of mTECs in the Tnfrsf11a−/−CD40−/− mice. Thymic stroma transplantation would help to further clarify the cooperative regulation of RANK and CD40 signals directly on mTEC development. Another interesting question might be whether LTβR signaling plays a distinct role in mTEC development and participates in the synergistic regulation of mTECs with CD40 or RANK. It is of note that the RANKL-RANK signal appears to be the most potent single one among all the TNFRSF members thus tested (Hikosaka et al., 2008Hikosaka Y. Nitta T. Ohigashi I. Yano K. Ishimaru N. Hayashi Y. Matsumoto M. Matsuo K. Penninger J.M. Takayanagi H. et al.Immunity. 2008; 29 (this issue): 438-450Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar). It remains largely unclear which cells produce the ligand for signaling. Although previous studies suggested an essential role of positively selected thymocytes in the development of mTECs (Surh et al., 1992Surh C.D. Ernst B. Sprent J. J. Exp. Med. 1992; 176: 611-616Crossref PubMed Scopus (112) Google Scholar), recent work demonstrated an important role of lymphoid tissue inducer (LTi) cells for the generation of Aire+ mTECs (Rossi et al., 2007Rossi S.W. Kim M.-Y. Leibbrandt A. Parnell S.M. Jenkinson W.E. Glanville S.H. McConnell F.M. Scott H.S. Penninger J.M. Jenkinson E.J. et al.J. Exp. Med. 2007; 204: 1267-1272Crossref PubMed Scopus (347) Google Scholar). However, the earlier study analyzed only thymic medulla but not mTECs, and in the latter study, it is unknown whether LTi cells are essential for mTEC development although they are found sufficient to do so in an in vitro FTOC experimental model. In the study of Hikosaka et al., 2008Hikosaka Y. Nitta T. Ohigashi I. Yano K. Ishimaru N. Hayashi Y. Matsumoto M. Matsuo K. Penninger J.M. Takayanagi H. et al.Immunity. 2008; 29 (this issue): 438-450Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar in this issue, by using specific antibodies against mTECs and Aire, the authors revisited mTEC development in mice lacking positive selection (Tcra−/−, Zap70−/−, and Rag2−/−) and confirmed the reduced number of mTECs. A dispensable role for Id2-dependent LTi cells in mTEC development was also directly revealed in Id2−/− mice, in contrast to Rossi et al., 2007Rossi S.W. Kim M.-Y. Leibbrandt A. Parnell S.M. Jenkinson W.E. Glanville S.H. McConnell F.M. Scott H.S. Penninger J.M. Jenkinson E.J. et al.J. Exp. Med. 2007; 204: 1267-1272Crossref PubMed Scopus (347) Google Scholar. However, it is not clear how positively selected thymocytes control mTEC development. One mechanism could be via RANK-mediated mTEC proliferation, because the frequency of proliferating mTECs was found to be substantially elevated when the RANKL signal was forcefully delivered. In a more physiological model, positively selected CD4+ SP and CD8+ SP thymocytes but not DP thymocytes were found to be able to increase mTEC numbers in a reaggregated thymic organ culture experiment, and the induction could be diminished by RANK-Fc blockade. In accordance with the Akiyama et al., 2008Akiyama T. Shimo Y. Yanai H. Qin J. Ohshima D. Maruyama Y. Asaumi Y. Kitazawa J. Takayanagi H. Penninger J.M. et al.Immunity. 2008; 29 (this issue): 423-437Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar study, an additional role of signals other than RANK was also suggested. What is the respective role of CD4+ and CD8+ SP thymocytes? And what are the special properties of those SP cells for regulating mTEC development? Irla et al., 2008Irla M. Hugues S. Gill J. Nitta T. Hikosaka Y. Williams I.R. Hubert F.-X. Scott H.S. Takahama Y. Holländer G.A. Reith W. Immunity. 2008; 29 (this issue): 451-463Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar in this issue have first found that the CD4+ SP but not CD8+ SP thymocytes are required for the development of mTECs and appear to contribute by increasing proliferation but not by reducing apoptosis. Furthermore, taking advantage of the cell-type-specific promoters controlling transcription of the gene encoding CIITA, the MHCII transactivator, the authors created an elegant animal model to maintain the positive selection of CD4+ SP thymocytes while ablating the interaction between CD4+ SP thymocytes and mTECs. With this model, the authors were able to reveal the role of direct MHCII-TCR interaction but not soluble factors for mTEC expansion. Interestingly, the autoantigen-specific interaction (autoreactivity) of CD4+ SP thymocytes seems critical for at least mature mTEC expansion, because OT-II-RIP-mOVAtg mice on Rag2−/− background demonstrate substantially more mature mTECs than OT-II mice on Rag2−/− background. This conclusion was also supported via Marilyn TCR transgenic mice, which express an MHCII-restricted TCR recognizing the male-specific antigen H-Y. It was not clear whether immature mTEC expansion also needs autoantigen-specific interaction between CD4+ SP thymocytes and mTECs. This question becomes interesting considering the fact that immature mTECs express much lower amounts of TRAs than do mature mTECs. The potential role of non-antigen-specific interaction on mTEC expansion was, however, not fully addressed. The comparison of OT-II-Rag2−/− and Rag2−/− mTECs would help to clarify this issue. It will also be interesting to see whether such interaction exists in CD8+ cells because of the potential killing effect of CD8+ cells on antigen+ mTECs. Although LTi cells are not the RANKL-producing cells for mTEC development in adult mice, the study of Akiyama et al., 2008Akiyama T. Shimo Y. Yanai H. Qin J. Ohshima D. Maruyama Y. Asaumi Y. Kitazawa J. Takayanagi H. Penninger J.M. et al.Immunity. 2008; 29 (this issue): 423-437Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar does show an essential role of RANK on mTEC development at the embryo stage. Then, the question is raised what cells provide the RANKL for mTEC development at the embryonic stage. Given the relative later appearance of αβ T cell (E16–17), LTi cells are likely to be the major RANKL-producing cells. γδ T cells are also RANKL-expressing cells that are generated much earlier than αβ T cell. However, their essential role has also been excluded by Hikosaka et al., 2008Hikosaka Y. Nitta T. Ohigashi I. Yano K. Ishimaru N. Hayashi Y. Matsumoto M. Matsuo K. Penninger J.M. Takayanagi H. et al.Immunity. 2008; 29 (this issue): 438-450Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar via Tcrd−/− mice. The possibility that LTi cells serve as RANKL-producing cells at the embryo stage would be consistent with previous finding (Rossi et al., 2007Rossi S.W. Kim M.-Y. Leibbrandt A. Parnell S.M. Jenkinson W.E. Glanville S.H. McConnell F.M. Scott H.S. Penninger J.M. Jenkinson E.J. et al.J. Exp. Med. 2007; 204: 1267-1272Crossref PubMed Scopus (347) Google Scholar) in which LTi cells were indicated to promote mTEC maturation. The data of these three studies have substantially extended our current understanding of the development of mTECs at both cellular and molecular levels as delineated in Figure 1. However, many questions still remain elusive. One primary question is how the TNFRSF signals work. This question needs to be addressed for embryonic and postnatal thymus separately, because they might exert their roles in different checkpoints, e.g., mTEC differentiation, maturation, expansion, or organization. The exact role of different TNFRSF signals also remains to be determined. Second, how does the antigen-specific MHC-TCR interaction regulate mTEC development and function? If TCR specificity prolongs the CD40 and RANK signaling effect, does this mean that the TRA-expressing cell would have prolonged survival or proliferation? However, this hypothesis would be difficult to reconcile with previous findings that Aire+ mTECs have arrested proliferation and that Aire actually induces apoptosis in Aire-expressing mTECs (Gray et al., 2007Gray D. Abramson J. Benoist C. Mathis D. J. Exp. Med. 2007; 204: 2521-2528Crossref PubMed Scopus (267) Google Scholar). If autoreactive T cells are required for the specific deletion of TRA-expressing mTEC, given the diversity of TRAs in the individual mTEC, how are other TRAs maintained? Further studies are required to understand mTEC development and function in more detail and to explore potential therapeutic interventions. The Tumor Necrosis Factor Family Receptors RANK and CD40 Cooperatively Establish the Thymic Medullary Microenvironment and Self-ToleranceAkiyama et al.ImmunitySeptember 19, 2008In BriefMedullary thymic epithelial cells (mTECs) establish T cell self-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specific self-antigens. However, signals underlying mTEC development remain largely unclear. Here, we demonstrate crucial regulation of mTEC development by receptor activator of NF-κB (RANK) and CD40 signals. Whereas only RANK signaling was essential for mTEC development during embryogenesis, in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development to successfully establish the medullary microenvironment. Full-Text PDF Open ArchiveThe Cytokine RANKL Produced by Positively Selected Thymocytes Fosters Medullary Thymic Epithelial Cells that Express Autoimmune RegulatorHikosaka et al.ImmunitySeptember 19, 2008In BriefThe thymic medulla provides a microenvironment where medullary thymic epithelial cells (mTECs) express autoimmune regulator and diverse tissue-restricted genes, contributing to launching self-tolerance. Positive selection is essential for thymic medulla formation via a previously unknown mechanism. Here we show that the cytokine RANK ligand (RANKL) was produced by positively selected thymocytes and regulated the cellularity of mTEC by interacting with RANK and osteoprotegerin. Forced expression of RANKL restored thymic medulla in mice lacking positive selection, whereas RANKL perturbation impaired medulla formation. Full-Text PDF Open ArchiveAutoantigen-Specific Interactions with CD4+ Thymocytes Control Mature Medullary Thymic Epithelial Cell CellularityIrla et al.ImmunitySeptember 19, 2008In BriefMedullary thymic epithelial cells (mTECs) are specialized for inducing central immunological tolerance to self-antigens. To accomplish this, mTECs must adopt a mature phenotype characterized by expression of the autoimmune regulator Aire, which activates the transcription of numerous genes encoding tissue-restricted self-antigens. The mechanisms that control mature Aire+ mTEC development in the postnatal thymus remain poorly understood. We demonstrate here that, although either CD4+ or CD8+ thymocytes are sufficient to sustain formation of a well-defined medulla, expansion of the mature mTEC population requires autoantigen-specific interactions between positively selected CD4+ thymocytes bearing autoreactive T cell receptor (TCR) and mTECs displaying cognate self-peptide-MHC class II complexes. Full-Text PDF Open Archive
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