Toll is the founder of a group of pattern recognition receptors that play a critical role in the innate immunity in Drosophila. At least 10 distinct Toll-like receptors (TLRs), recognizing pathogen-associated molecular patterns, have now been identified in humans. Most investigations on TLRs have focused on cells of the innate system. We report here that naïve human T cells expressed high levels of cellsurface TLR2 after activation by anti-T cell receptor antibody and IFN-␣. Activated cells produced elevated levels of cytokines in response to the TLR2 ligand, bacterial lipopeptide. Furthermore, CD4 ؉ CD45RO ؉ memory T cells from peripheral blood constitutively expressed TLR2 and produced IFN-␥ in response to bacterial lipopeptide, which also markedly enhanced the proliferation and IFN-␥ production by CD45RO ؉ T cells in the presence of IL-2 or IL-15. Thus, TLR2 serves as a costimulatory receptor for antigen-specific T cell development and participates in the maintenance of T cell memory. This suggests that pathogens, via their pathogen-associated molecular patterns, may contribute directly to the perpetuation and activation of long-term T cell memory in both antigen-dependent and independent manner.

NCT01523353 (https://clinicaltrials.gov).

The cytotoxic T-cell response in chronic hepatitis B virus (HBV) infection has been described as weak and mono-or oligospecific in comparison to the more robust virus-specific T-cell response present in resolved infection. However, chronic hepatitis B is a heterogeneous disease with markedly variable levels of virus replication and liver disease activity. Here we analyzed (both directly ex vivo and after in vitro stimulation) the HBV-specific CD8 T-cell responses against structural and nonstructural HBV proteins longitudinally in patients with different patterns of chronic infections. We found that the profiles of virus-specific CD8؉ -T-cell responses during chronic infections are highly heterogeneous and influenced more by the level of HBV replication than by the activity of liver disease. An HBV DNA load of <10 7 copies/ml appears to be the threshold below which circulating multispecific HBV-specific CD8 ؉ T cells are consistently detected. Furthermore, CD8؉ T cells with different specificities are differentially regulated during chronic infections. HBV core-specific CD8 ؉ T cells are associated with viral control, while CD8 ؉ T cells specific for envelope and polymerase epitopes can occasionally be found in the setting of high levels (>10 7 copies) of HBV replication. These findings have implications for the design of immunotherapy for chronic HBV infections.

We intended to identify the prognostic factors and the results of interventions on patients with liver metastatic midgut carcinoids. Five institutions that are part of United Kingdom and Ireland neuroendocrine tumour (NET) group took part in this study. Patients were included if they had histology proven NET of midgut origin and liver metastases at the time of the study. Clinical and biochemical data were collected retrospectively from hospital charts, pathology reports, radiology reports and biochemistry records for each patient. Three hundred and sixty patients were included in the study. The median survival from date of diagnosis was 7.69 years (confidence interval (CI) 6.40-8.99) and 5.95 years (CI 5.02-6.88) from date of diagnosis of liver metastases. On univariate analysis, increasing age at diagnosis, increasing urinary hydroxyindole acetic acid levels, increasing plasma chromogranin A levels, high Ki67, high tumour volume and treatment with chemotherapy were identified as factors associated with a significantly poorer outcome. Resection of liver metastases, resection of small bowel primary, treatment with somatostatin analogue therapy and treatment with peptide receptor therapy were associated with improved prognosis. Multivariate analysis revealed that age at diagnosis (PZ0.014), Ki67 level (PZ0.039) and resection of primary (PZ0.015) were independent predictors of survival. This is the largest study to our knowledge looking specifically at the prognosis and clinical course of patients with liver metastatic midgut NETs. For the first time, we have shown that Ki67 and resection of primary are independent predictors of survival for this group of patients.