Competition for Antigen at the Level of the APC Is a Major Determinant of Immunodominance during Memory Inflation in Murine Cytomegalovirus Infection

The unique ability of CMV to drive the expansion of virus-specific T cell populations during the course of a lifelong, persistent infection has generated interest in the virus as a potential vaccine strategy. When designing CMV-based vaccine vectors to direct immune responses against HIV or tumor Ags, it becomes important to understand how and why certain CMV-specific populations are chosen to inflate over time. To investigate this, we designed recombinant murine CMVs (MCMVs) encoding a SIINFEKL-enhanced GFP fusion protein under the control of endogenous immediate early promoters. When mice were infected with these viruses, T cells specific for the SIINFEKL epitope inflated and profoundly dominated T cells specific for nonrecombinant (i.e., MCMV-derived) Ags. Moreover, when the virus encoded SIINFEKL, T cells specific for nonrecombinant Ags displayed a phenotype indicative of less frequent exposure to Ag. The immunodominance of SIINFEKL-specific T cells could not be altered by decreasing the number of SIINFEKL-specific cells available to respond, or by increasing the number of cells specific for endogenous MCMV Ags. In contrast, coinfection with viruses expressing and lacking SIINFEKL enabled coinflation of T cells specific for both SIINFEKL and nonrecombinant Ags. Because coinfection allows presentation of SIINFEKL and MCMV-derived Ags by different cells within the same animal, these data reveal that competition for, or availability of, Ag at the level of the APC determines the composition of the inflationary response to MCMV. SIINFEKL\u27s strong affinity for H-2K(b), as well as its early and abundant expression, may provide this epitope\u27s competitive advantage

Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure.

Vδ2+ γδ T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vδ2+ T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vδ2+ counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n = 377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower Vδ2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished Vδ2+ T cell pro-inflammatory cytokine production. Higher Vδ2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. Vδ2+ T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria

Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein

Interferon (IFN) consensus sequence-binding protein/IFN regulatory factor 8 (IRF8) is a transcription factor that regulates the differentiation and function of macrophages, granulocytes, and dendritic cells through activation or repression of target genes. Although IRF8 is also expressed in lymphocytes, its roles in B cell and T cell maturation or function are ill defined, and few transcriptional targets are known. Gene expression profiling of human tonsillar B cells and mouse B cell lymphomas showed that IRF8 transcripts were expressed at highest levels in centroblasts, either from secondary lymphoid tissue or transformed cells. In addition, staining for IRF8 was most intense in tonsillar germinal center (GC) dark-zone centroblasts. To discover B cell genes regulated by IRF8, we transfected purified primary tonsillar B cells with enhanced green fluorescent protein–tagged IRF8, generated small interfering RNA knockdowns of IRF8 expression in a mouse B cell lymphoma cell line, and examined the effects of a null mutation of IRF8 on B cells. Each approach identified activation-induced cytidine deaminase (AICDA) and BCL6 as targets of transcriptional activation. Chromatin immunoprecipitation studies demonstrated in vivo occupancy of 5′ sequences of both genes by IRF8 protein. These results suggest previously unappreciated roles for IRF8 in the transcriptional regulation of B cell GC reactions that include direct regulation of AICDA and BCL6

Épisodes d’inactivité et revenus criminels dans une trajectoire de délinquance

L’instabilité de l’activité criminelle dans le temps est déjà bien documentée. On connaît toutefois peu les circonstances qui expliquent ces variations à court terme. Une meilleure connaissance de ces facteurs est souhaitable puisqu’il est possible que les transitions et les changements à court terme précèdent les points tournants des carrières criminelles. Les conditions qui rendent compte d’une interruption temporaire des activités peuvent, par exemple, contribuer à expliquer un désistement définitif. L’étude se fonde sur les trajectoires de 172 délinquants impliqués dans des crimes à but lucratif et analyse les variations mensuelles de leurs revenus criminels ainsi que les épisodes d’inactivité criminelle à l’intérieur d’une période fenêtre de 36 mois. La méthode des calendriers d’histoire de vie combinée aux modèles hiérarchiques permet d’examiner conjointement le rôle de facteurs statiques (les caractéristiques individuelles des sujets) et dynamiques (les circonstances de vie). Les résultats mettent en évidence l’importance des événements qui marquent le style de vie des délinquants et des paramètres qui caractérisent l’engagement criminel dans la compréhension des variations dans les trajectoires à l’étude. Ils soulignent également l’importance de la finalité derrière les activités criminelles pour expliquer la décision des délinquants de cesser temporaire leurs activités illicites

Developmental and Life-Course Criminology

This chapter provides a brief overview of developmental and life-course criminology. These approaches are concerned with the study of the development of offending over the course of one's life, from onset to persistence and, eventually, desistance. Although these two theoretical approaches share many common features, they have distinctive focal concerns. Stemming from the field of sociology, the life-course perspective focuses attention on social structure and life events. The developmental approach, on the other hand, stems from the field of psychology and generally emphasizes the role of individual and psychological factors in the explanation of developmental processes. Moreover, the developmental approach investigates the onset of offending as well as the role of early risk and protective factors in the explanation of future offending. Meanwhile, the life-course framework examines the influence of turning points in offending trajectories and in the process of desistance from crime