Early degenerate selection of thymocytes by class I major histocompatibility complex

Ontogeny of T cells is accomplished in the thymus by a process of positive selection, in which interaction of the T cell receptor (TcR) expressed on CD4+8+ thymocytes with self major histocompatibility complex (MHC), expressed on cortical epithelial cells, determines the progress along the maturation pathway and confers self restriction to T cells. Conversely, cells behaving as self reactive by interaction with bone marrow-derived antigen-presenting cells are negatively selected by apoptosis. We show here that the presence of a class I-restricted soluble TcR (sTcR) in the fetal thymic microenvironment, early in T cell ontogeny, determines an enhanced negative selection of a sizeable number of CD4+8+ thymocytes, which have been previously subjected to a positive-selection event. We hypothesize that the generation of the mature thymic T cell repertoire stems from an interaction of TcR, under a critical affinity threshold, with a self peptide-MHC complex which is common to a great number of TcR specificities using the same restriction element. A shift in this affinity threshold, caused by sTcR, results in the generation of cells acting in a self-reactive manner, which are then deleted. In extended fetal thymus organ culture in the presence of sTcR, we have also observed the appearance of mature CD8+ T cells,which once adoptively transferred to syngeneic nude mice are expanded in the periphery, consistent with an enhanced avidity of these cells for self MHC

Surface expression and functional competence of CD3-independent TCR \u3b6-chains in immature thymocytes

In recombinase-deficient (RAG-2(-/-)) mice, double-negative thymocytes can be stimulated to proliferate and differentiate by anti-CD3 Abs. CD3 molecules are expressed on the surface of these cells in association with calnexin. In this study, we show that \u3b6-chains can be recovered as phosphorylated proteins in association with phosphorylated ZAP-70 from anti- CD3-stimulated RAG-2(-/-) thymocytes, even though they are not demonstrably associated with the CD3/calnexin complex. The lack of a physical association of \u3b6 dimers with the CD3 complex in RAG-2(-/-) thymocytes and also in a pre- TCR-expressing cell line, as well as the efficient association of \u3b6 dimers with ZAP-70 in the RAG-2(-/-) thymocytes, suggest that these \u3b6-chain dimers could contribute to pre-TCR signaling. This idea is supported by the finding that in RAG-2(-/-) \u3b6-deficient thymocytes, ZAP-70 and p120(cbl) were only weakly phosphorylated

Predictors of circulating vitamin D levels in healthy mid-life Singaporean women

10.1007/s11657-021-00880-2ARCHIVES OF OSTEOPOROSIS16

Randomized, double-blind, placebo-controlled trial to examine the safety, pharmacokinetics and effects of Epimedium prenylflavonoids, on bone specific alkaline phosphatase and the osteoclast adaptor protein TRAF6 in post-menopausal women

10.1016/j.phymed.2021.153680PHYTOMEDICINE9

Leporid immunoglobulin G shows evidence of strong selective pressure on the hinge and CH3 domains

Immunoglobulin G (IgG) is the predominant serum immunoglobulin and has the longest serum half-life of all the antibody classes. The European rabbit IgG has been of significant importance in immunological research, and is therefore well characterized. However, the IgG of other leporids has been disregarded. To evaluate the evolution of this gene in leporids, we sequenced the complete IGHG for six other genera: Bunolagus, Brachylagus, Lepus, Pentalagus, Romerolagus and Sylvilagus. The newly sequenced leporid IGHGgene has an organization and structure similar to that of the European rabbit IgG. A gradient in leporid IgG constant domain diversity was observed, with the CH1 being the most conserved and the CH3 the most variable domain. Positive selectionwas found to be acting on all constant domains, but with a greater incidence in the CH3 domain, where a cluster of three positively selected siteswas identified. In the hinge region, only three polymorphic positions were observed. The same hinge length was observed for all leporids. Unlike the variation observed for the European rabbit, all 11 Lepus species studied share exactly the same hinge motif, suggesting its maintenance as a result of an advantageous structure or conformation.The Portuguese Foundation for Science and Technology (FCT) supported the doctoral fellowship of A.P. (SFRH/BD/71252/2010); J.A. is supported by an FCT Investigator grant no. IF/01396/2013. This work was partially funded by FEDER (Fundo Europeu de Desenvolvimento Regional) funds through the Programa Operacional Factores de Competitividade (COMPETE programme; FCOMP-01–0124-FEDER-028286) and Portuguese national funds through FCT (research project PTDC/BIA-ANM/3963/2012)–Quadro de Referência Estratégico Nacional (QREN) funds from the European Social Fund and Portuguese Ministério da Educaçao e Ciência. ‘Genomics Applied to Genetic Resources’, cofinanced by North Portugal Regional Operational Programme 2007/2013 (ON.2—O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF), supported this work.Peer Reviewe