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Redefining thymus medulla specialization for central tolerance.

ABSTRACT: During ??T cell development, the thymus medulla represents an essential microenvironment for T cell tolerance. This functional specialization is attributed to its typical organized topology consisting of a branching structure that contains medullary thymic epithelial cell (mTEC) networks to support negative selection and Foxp3⁺ T-regulatory cell (T-reg) development. Here, by performing TEC-specific deletion of the thymus medulla regulator lymphotoxin ? receptor (LT?R), we show that thymic tolerance mechanisms operate independently of LT?R-mediated mTEC development and organization. Consistent with this, mTECs continue to express Fezf2 and Aire, regulators of intrathymic self-antigens, and support T-reg development despite loss of LT?R-mediated medulla organogenesis. Moreover, we demonstrate that LT?R controls thymic tolerance by regulating the frequency and makeup of intrathymic dendritic cells (DCs) required for effective thymocyte negative selection. In all, our study demonstrates that thymus medulla specialization for thymic tolerance segregates from medulla organogenesis and instead involves LT?R-mediated regulation of the thymic DC pool.

SUBMITTER: Cosway EJ

PROVIDER: S-EPMC5679166 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Redefining thymus medulla specialization for central tolerance.

Cosway Emilie J EJ Lucas Beth B James Kieran D KD Parnell Sonia M SM Carvalho-Gaspar Manuela M White Andrea J AJ Tumanov Alexei V AV Jenkinson William E WE Anderson Graham G

The Journal of experimental medicine 20170822 11

During αβT cell development, the thymus medulla represents an essential microenvironment for T cell tolerance. This functional specialization is attributed to its typical organized topology consisting of a branching structure that contains medullary thymic epithelial cell (mTEC) networks to support negative selection and Foxp3<sup>+</sup> T-regulatory cell (T-reg) development. Here, by performing TEC-specific deletion of the thymus medulla regulator lymphotoxin β receptor (LTβR), we show that th ...[more]

PMID: 28830910

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Project description:With about 68 recognized living species, subterranean rodents of the genus Ctenomys are found in a multiplicity of habitats, from the dunes of the Atlantic coast to the Andes Mountains, including environments ranging from humid steppes of Pampas to the dry deserts of Chaco region. However, this genus needs an exhaustive reevaluation of its systematic and phylogenetic relationships regarding the different groups that compose it. This knowledge is essential to propose biodiversity conservation strategies both at species level and at higher hierarchical levels. In order to clarify the taxonomy and the recent evolutionary history from populations of Ctenomys in the Pampas region, Argentina, phylogenetic relationships among them were evaluated using mitochondrial DNA sequences: gene encoding cytochrome b protein (1,140 bp) and the non-coding D-loop region (434 bp). To infer the divergence times inside the Ctenomys clade, a Bayesian calibrate tree using fossil remains data from different families within Caviomorpha was performed at first. Secondly, that calibration data was used as priors in a new Bayesian phylogenetic inference within the genus Ctenomys. This phylogenetic tree emphasized on species currently distributed on the Pampas region, more precisely considering both the talarum and mendocinus groups. Bayesian inferences (BI) were integrated with the results of a Maximum Likelihood approach (ML). Based on these results, the distributional limits of the mendocinus and talarum groups appear to be related to the physiognomy of the Pampas region soils. On the other hand, the validity of C. pundti complex as a differentiated species of C. talarum is debated. According to previous evidence from morphological and chromosomal studies, these results show a very low divergence between those species that originally were classified within the talarum group. Mitochondrial DNA sequences from populations associated with these putative species have not recovered as reciprocal monophyletic groups in the phylogenetic analyses. In conclusion, C. talarum and C. pundti complex might be considered as the same biological species, or lineages going through a recent or incipient differentiation process. The results obtained in this study have important implications for conservation policies and practices, since both species are currently categorized as Vulnerable and Endangered, respectively.

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Redefining thymus medulla specialization for central tolerance.

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Redefining thymus medulla specialization for central tolerance.

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