What Is Direct Allorecognition?

Direct allorecognition is the process by which donor-derived major histocompatibility complex (MHC)-peptide complexes, typically presented by donor-derived ‘passenger’ dendritic cells, are recognised directly by recipient T cells. In this review, we discuss the two principle theories which have been proposed to explain why individuals possess a high-precursor frequency of T cells with direct allospecificity and how self-restricted T cells recognise allogeneic MHCpeptide complexes. These theories, both of which are supported by functional and structural data, suggest that T cells recognising allogeneic MHC-peptide complexes focus either on the allopeptides bound to the allo-MHC molecules or the allo-MHC molecules themselves. We discuss how direct alloimmune responses may be sustained long term, the consequences of this for graft outcome and highlight novel strategies which are currently being investigated as a potential means of reducing rejection mediated through this pathway

Structure of a carbohydrate esterase from Bacillus anthracis

Family 4 carbohydrate esterases (CEs) catalyse the N- or O-deacetylation of substrates such as acetylated xylan, chitin, and peptidoglycan. CEs are classified into 14 families by sequence homology (see http://afmb.cnrs-mrs.fr/CAZY1). Family 4 is by far the largest of the CE families, with over 1000 open reading frames. The structure of CE4 enzymes from a number of bacterial species have been solved, including the peptidoglycan deacetylases from Streptococcus pneumoniae and Bacillus subtilis,3 acetyl xylan esterases from Clostridium thermocellum and Streptomyces lividans,4 and an enzyme of unknown specificity from Pseudomonas aeruginosa (PDBcode 1Z7A). CE4 enzymes contain a conserved NodB homology domain, and adopt a distorted (a/b)8 barrel fold. Most of the structures contain a divalent ion in the active site that is necessary for enzyme activity2,4 and which is coordinated by highly conserved histidine and aspartate residues

Transducer Binding Establishes Localized Interactions to Tune Sensory Rhodopsin II

SummaryIn haloarchaea, sensory rhodopsin II (SRII) mediates a photophobic response to avoid photo-oxidative damage in bright light. Upon light activation the receptor undergoes a conformational change that activates a tightly bound transducer molecule (HtrII), which in turn by a chain of homologous reactions transmits the signal to the chemotactic eubacterial two-component system. Here, using single-molecule force spectroscopy, we localize and quantify changes to the intramolecular interactions within SRII of Natronomonas pharaonis (NpSRII) upon NpHtrII binding. Transducer binding affected the interactions at transmembrane α helices F and G of NpSRII to which the transducer was in contact. Remarkably, the interactions were distributed asymmetrically and significantly stabilized α helix G entirely but α helix F only at its extracellular tip. These findings provide unique insights into molecular mechanisms that “prime” the complex for signaling, and guide the receptor toward transmitting light-activated structural changes to its cognate transducer

Graft-versus-host disease is locally maintained in target tissues by resident progenitor-like T cells.

In allogeneic hematopoietic stem cell transplantation, donor αβ T cells attack recipient tissues, causing graft-versus-host disease (GVHD), a major cause of morbidity and mortality. A central question has been how GVHD is sustained despite T cell exhaustion from chronic antigen stimulation. The current model for GVHD holds that disease is maintained through the continued recruitment of alloreactive effectors from blood into affected tissues. Here, we show, using multiple approaches including parabiosis of mice with GVHD, that GVHD is instead primarily maintained locally within diseased tissues. By tracking 1,203 alloreactive T cell clones, we fitted a mathematical model predicting that within each tissue a small number of progenitor T cells maintain a larger effector pool. Consistent with this, we identified a tissue-resident TCF-1 <sup>+</sup> subpopulation that preferentially engrafted, expanded, and differentiated into effectors upon adoptive transfer. These results suggest that therapies targeting affected tissues and progenitor T cells within them would be effective