KIR-HLA interactions extend human CD8+ T cell lifespan in vivo

BACKGROUND. There is increasing evidence, in transgenic mice and in vitro, that inhibitory killer cell immunoglobulin-like receptors (iKIRs) can modulate T cell responses. Furthermore, we have previously shown that iKIRs are an important determinant of T cell–mediated control of chronic viral infection and that these results are consistent with an increase in the CD8+ T cell lifespan due to iKIR-ligand interactions. Here, we tested this prediction and investigated whether iKIRs affect T cell lifespan in humans in vivo. METHODS. We used stable isotope labeling with deuterated water to quantify memory CD8+ T cell survival in healthy individuals and patients with chronic viral infections. RESULTS. We showed that an individual’s iKIR-ligand genotype was a significant determinant of CD8+ T cell lifespan: in individuals with 2 iKIR-ligand gene pairs, memory CD8+ T cells survived, on average, for 125 days; in individuals with 4 iKIR-ligand gene pairs, the memory CD8+ T cell lifespan doubled to 250 days. Additionally, we showed that this survival advantage was independent of iKIR expression by the T cell of interest and, further, that the iKIR-ligand genotype altered the CD8+ and CD4+ T cell immune aging phenotype. CONCLUSIONS. Together, these data reveal an unexpectedly large effect of iKIR genotype on T cell survival

KIR-HLA interactions extend human CD8+ T cell lifespan in vivo.

BACKGROUND: There is increasing evidence, in transgenic mice and in vitro, that inhibitory killer cell immunoglobulin-like receptors (iKIRs) can modulate T cell responses. Furthermore, we have previously shown that iKIRs are an important determinant of T cell-mediated control of chronic virus infection and that these results are consistent with an increase in CD8+ T cell lifespan due to iKIR-ligand interactions. Here we test this prediction and investigate whether iKIRs affect T cell lifespan in humans in vivo. METHODS: We used stable isotope labelling with deuterated water to quantify memory CD8+ T cell survival in healthy individuals and patients with chronic viral infections. RESULTS: We showed that an individual's iKIR-ligand genotype is a significant determinant of CD8+ T cell lifespan: in individuals with two iKIR-ligand gene pairs, memory CD8+ T cells survived on average for 125 days, in individuals with four iKIR-ligand gene pairs then memory CD8+ T cell lifespan was doubled to 250 days. Additionally, we showed that this survival advantage is independent of iKIR expression by the T cell of interest and further that iKIR-ligand genotype altered CD8+ and CD4+ T cell immune aging phenotype. CONCLUSIONS: Together these data reveal an unexpectedly large impact of iKIR genotype on T cell survival. FUNDING: Wellcome Trust, Medical Research Council, EU Horizon 2020, EU FP7, Leukemia and Lymphoma Research, National Institute of Health Research Imperial Biomedical Research Centre, Imperial College Research Fellowship, National Institute of Health, Jefferiss Trust

Large Proteins Have a Great Tendency to Aggregate but a Low Propensity to Form Amyloid Fibrils

The assembly of soluble proteins into ordered fibrillar aggregates with cross-β structure is an essential event of many human diseases. The polypeptides undergoing aggregation are generally small in size. To explore if the small size is a primary determinant for the formation of amyloids under pathological conditions we have created two databases of proteins, forming amyloid-related and non-amyloid deposits in human diseases, respectively. The size distributions of the two protein populations are well separated, with the systems forming non-amyloid deposits appearing significantly larger. We have then investigated the propensity of the 486-residue hexokinase-B from Saccharomyces cerevisiae (YHKB) to form amyloid-like fibrils in vitro. This size is intermediate between the size distributions of amyloid and non-amyloid forming proteins. Aggregation was induced under conditions known to be most effective for amyloid formation by normally globular proteins: (i) low pH with salts, (ii) pH 5.5 with trifluoroethanol. In both situations YHKB aggregated very rapidly into species with significant β-sheet structure, as detected using circular dichroism and X-ray diffraction, but a weak Thioflavin T and Congo red binding. Moreover, atomic force microscopy indicated a morphology distinct from typical amyloid fibrils. Both types of aggregates were cytotoxic to human neuroblastoma cells, as indicated by the MTT assay. This analysis indicates that large proteins have a high tendency to form toxic aggregates, but low propensity to form regular amyloid in vivo and that such a behavior is intrinsically determined by the size of the protein, as suggested by the in vitro analysis of our sample protein

Testicular extramedullary plasmacytoma

Extramedullary plasmacytomas are plasma cell tumors that arise outside the bone marrow. They are most often located in the head and neck. Extramedullary plasmacytomas account for approximately 3 percent of plasma cell malignancies. The diagnosis of an extramedullary plasmacytoma depends upon the demonstration of a monoclonal plasma cell tumor at an extramedullary site with no evidence of multiple myeloma based upon bone marrow examination and roentgenographic studies, absence of an M-protein in serum and/ or urine, and no related organ or tissue impairment. These tumors are highly responsive to local radiation therapy and rarely progress or recur. A 77 year old man referred for gradual enlargement of scrotum in April, 2004. He had no fever, weight loss or loss of appetite during the period. No tenderness, warmth or erythem of scrotum was observed on physical examination. No lymphadenopathy was detected. Later he had temporary relief because of antibiotic therapy . 7 months later, he referred again following the aggravation of his symptom. Ultrasonography of his scrotum was done and enlargement in the left testis was reported. Lab data including CBC,diff,ESR,AFP were normal but βHCG titer was reported higher than normal . He underwent radical orchiectomy and the specimen was sent for pathological study. Spermatocytic seminoma and plasmacytoma were suspected, but plasmacytoma was reported after the IHC . In order to rule out multiple myeloma, whole body bone scanning with sestamibi and urine Bence Jones protein were examined, all of which were negative. In bone marrow aspiration, the cellularity was normal and no pathologic lesion was reported. Considering clinical and paraclinical evidences, the diagnosis was extramedullary plasmacytoma

Targeted cell detection based on microchannel gating

Currently, microbiological techniques such as culture enrichment and various plating techniques are used for detection of pathogens. These expensive and time consuming methods can take several days. Described below is the design, fabrication, and testing of a rapid and inexpensive sensor, involving the use of microelectrodes in a microchannel, which can be used to detect single bacterial cells electrically (label-free format) in real time. As a proof of principle, we have successfully demonstrated real-time detection of target yeast cells by measuring instantaneous changes in ionic impedance. We have also demonstrated the selectivity of our sensors in responding to target cells while remaining irresponsive to nontarget cells. Using this technique, it can be possible to multiplex an array of these sensors onto a chip and probe a complex mixture for various types of bacterial cells