Increased Memory Conversion of Naïve CD8 T Cells Activated during Late Phases of Acute Virus Infection Due to Decreased Cumulative Antigen Exposure

Background: Memory CD8 T cells form an essential part of protective immunity against viral infections. Antigenic load, costimulation, CD4-help, cytokines and chemokines fluctuate during the course of an antiviral immune response thus affecting CD8 T cell activation and memory conversion. Methodology/Principal Findings: In the present study, naïve TCR transgenic LCMV-specific P14 CD8 T cells engaged at a late stage during the acute antiviral LCMV response showed reduced expansion kinetics but greater memory conversion in the spleen. Such late activated cells displayed a memory precursor effector phenotype already at the peak of the systemic antiviral response, suggesting that the environment determined their fate during antigen encounter. In the spleen, the majority of late transferred cells exhibited a central memory phenotype compared to the effector memory displayed by the early transferred cells. Increasing the inflammatory response by exogenous administration of IFNc, PolyI:C or CpG did not affect memory conversion in the late transferred group, suggesting that the diverging antigen load early versus later during acute infection had determined their fate. In agreement, reduction in the LCMV antigenic load after ribavirin treatment enhanced the contribution of early transferred cells to the long lasting memory pool. Conclusions/Significance: Our results show that naïve CD8 cells, exposed to reduced duration or concentration of antigen during viral infection convert into memory more efficiently, an observation that could have significant implications fo

Bayesian Cue Integration as a Developmental Outcome of Reward Mediated Learning

Average human behavior in cue combination tasks is well predicted by Bayesian inference models. As this capability is acquired over developmental timescales, the question arises, how it is learned. Here we investigated whether reward dependent learning, that is well established at the computational, behavioral, and neuronal levels, could contribute to this development. It is shown that a model free reinforcement learning algorithm can indeed learn to do cue integration, i.e. weight uncertain cues according to their respective reliabilities and even do so if reliabilities are changing. We also consider the case of causal inference where multimodal signals can originate from one or multiple separate objects and should not always be integrated. In this case, the learner is shown to develop a behavior that is closest to Bayesian model averaging. We conclude that reward mediated learning could be a driving force for the development of cue integration and causal inference

Multi directional intertrochanteric osteotomy for primary and secondary osteoarthritis—results after 15 to 29 years

Between 1974 and 1987, 276 intertrochanteric osteotomies were performed in 217 patients. In 48 hips the osteotomy was done for idiopathic osteoarthritis. In 166 hips the osteoarthritis was secondary to acetabular dysplasia, in 23 to trauma, in 14 to slipped capital femoral epiphysis, in five to Legg–Calvé–Perthes' disease and in 20 to avascular necrosis of the femoral head. Good results were achieved in young females with mild osteoarthritis secondary to acetabular dysplasia, and in patients with posttraumatic osteoarthritis. All other indications showed a poorer long-term survival. Our study shows that acetabular dysplasia and posttraumatic arthritis remain valid indications for intertrochanteric osteotomy

Pharmacological Inhibition of TPL2/MAP3K8 Blocks Human Cytotoxic T Lymphocyte Effector Functions

CD8(+) cytotoxic T lymphocytes (CTLs) play a major role in defense against intracellular pathogens. During development, antigen-presenting cells secrete innate cytokines such as IL-12 and IFN-α, which drive CTL differentiation into diverse populations of effector and long-lived memory cells. Using whole transcriptome analyses, the serine/threonine protein kinase Tpl2/MAP3K8 was found to be induced by IL-12 and selectively expressed by effector memory (T(EM)) CTLs. Tpl2 regulates various inflammatory pathways by activating the ERK mediated MAP kinase pathway in innate immune cells such as macrophages and dendritic cells. In this study, we found that a specific small molecule Tpl2 inhibitor blocked IFN-γ and TNF-α secretion as well as cytolytic activity of human CTLs. This pathway was specific for human effector CTLs, as the Tpl2 inhibitor did not block IFN-γ and TNF-α secretion from murine effector CTLs. Further, IL-12 failed to induce expression of Tpl2 in murine CTLs, and Tpl2 deficient murine CTLs did not exhibit any functional deficiency either in vitro or in vivo in response to L. monocytogenes infection. In summary, we identified a species-specific role for Tpl2 in effector function of human CTLs, which plays a major role in adaptive immune responses to intracellular pathogens and tumors