Thymic positive and negative selection events generate a T-cell repertoire that is MHC restricted and self-tolerant. The number of T cells undergoing positive and negative selection in normal mice has never been firmly established. We generated mice that lack the proapoptotic molecule Bim (bcl2l11) together with a Nur77 GFP transgene, which allowed the identification and enumeration of T cells that would normally undergo clonal deletion. Using this method, we report the striking observation that six times more cells undergo negative selection than complete positive selection. Seventy-five percent of the negatively selected cells are deleted at the double positive stage in the thymic cortex, compared with 25% at the single positive stage in the medulla. The fact that more thymocytes are highly reactive to MHC than are weakly reactive is inconsistent with a random model of recognition and suggests that T-cell recognition is MHC biased. Furthermore, Bim −/− mice had an increased number of GFP hi cells in the peripheral lymphoid tissue and a corresponding increase in antigen experienced or anergic cell phenotype. Our data also show that the CD4+ T cells that are clonally deleted experienced only slightly stronger T-cell receptor signaling than those that developed into regulatory T cells.lymphocyte development | thymus P ositive and negative selection events in the thymus create a T-cell repertoire that is both major histocompatibility complex (MHC) restricted and self-tolerant. It is well established that the affinity of the T-cell receptor (TCR) for self-MHC ligands is critical in determining these fates. Low-affinity interactions promote survival and maturation, whereas high-affinity interactions promote deletion, with a surprisingly narrow threshold distinguishing these two (1). Nonetheless, it is unclear how many T-cell clones achieve this threshold and become deleted relative to the number that are positively selected. Because the T-cell receptor is formed by somatic recombination with nontemplated nucleotide addition, the amino acids in the antigen binding region are highly diverse and essentially random. Thus, it has been assumed that the number of clones that can interact with any given peptide MHC complex with high affinity (negative selection) would be smaller than the number of clones that could interact more weakly (positive selection). However, attempts to understand what fraction of the repertoire undergoes positive and negative selection have led to disparate findings.The murine thymus exports ∼1-4 × 10 6 cells per day, and these are predominantly naïve CD4 and CD8 T cells (2). Thus, based on the previous estimates of negative selection, one might predict that the number of self-reactive clones generated and deleted per day would be much smaller than this number. However, because apoptotic cells are so efficiently engulfed by thymic macrophages, it has been challenging to quantify clonal deletion. Consequently, the frequency with which clonal deletion occurs relative to positive selection has been co...

The design and synthesis of highly active oxygen reduction reaction (ORR) catalysts with strong durability at low cost is extremely desirable but still remains a significant challenge. Here we develop an efficient strategy that utilizes organopalladium(I) complexes containing palladium-palladium bonds as precursors for the synthesis of strongly coupled Pd tetrahedron-tungsten oxide nanosheet hybrids (Pd/W18O49) to improve the electrocatalytic activity and stability of Pd nanocrystals. The hybrid materials are synthesized by direct nucleation, growth, and anchoring of Pd tetrahedral nanocrystals on the in situ-synthesized W18O49 nanosheets. Compared to supportless Pd nanocrystals and W18O49, their hybrids exhibited not only surprisingly high activity but also superior stability to Pt for the ORR in alkaline solutions. X-ray photoelectron spectroscopy, high-resolution transmission electron microscopy, and electrochemical analyses indicated that the enhanced electrocatalytic activity and durability are associated with the increased number and improved catalytic activity of active sites, which is induced by the strong interaction between the Pd tetrahedrons and W18O49 nanosheet supports. The present study provides a novel strategy for synthesizing hybrid catalysts with strong chemical attachment and electrical coupling between nanocatalysts and supports. The strategy is expected to open up exciting opportunities for developing a novel class of metal-support hybrid nanoelectrocatalysts with improved ORR activity and durability for both fuel cells and metal-air batteries.

Positive selection occurs in the thymic cortex, but critical maturation events occur later in the medulla. We defined the precise stage at which T cells acquire competence to proliferate and emigrate. Transcriptome analysis of late gene changes suggested roles for NF-κB and interferon (IFN) signaling. Mice lacking the IKK kinase TAK1 underwent normal positive selection, but exhibited a specific block in functional maturation. NF-κB signaling provided protection from tumor necrosis factor (TNF) mediated death, and was required for proliferation and emigration. The interferon signature was independent of NF-κB, however IFN-αR–deficient thymocytes showed reduced STAT1 expression and phenotypic abnormality, but were competent to proliferate. Thus, both NF-κB and tonic IFN signals are involved in the final maturation of thymocytes into naïve T cells.

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