T Regulatory Cells Support Plasma Cell Populations in the Bone Marrow.

Long-lived plasma cells (PCs) in the bone marrow (BM) are a critical source of antibodies after infection or vaccination, but questions remain about the factors that control PCs. We found that systemic infection alters the BM, greatly reducing PCs and regulatory T (Treg) cells, a population that contributes to immune privilege in the BM. The use of intravital imaging revealed that BM Treg cells display a distinct behavior characterized by sustained co-localization with PCs and CD11c-YFP+ cells. Gene expression profiling indicated that BM Treg cells express high levels of Treg effector molecules, and CTLA-4 deletion in these cells resulted in elevated PCs. Furthermore, preservation of Treg cells during systemic infection prevents PC loss, while Treg cell depletion in uninfected mice reduced PC populations. These studies suggest a role for Treg cells in PC biology and provide a potential target for the modulation of PCs during vaccine-induced humoral responses or autoimmunity.

Common genetic variants modulate pathogen-sensing responses in human dendritic cells.

Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-ß (IFN-ß). We localized and validated causal variants to binding sites of pathogen-activated STAT (signal transducer and activator of transcription) and IRF (IFN-regulatory factor) transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I IFN induction in response to influenza infection. Our results reveal common alleles that explain interindividual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases.

Chromosomal clustering of genes controlled by the aire transcription factor.

Autoimmune regulator (aire) is a transcription factor that controls the self-reactivity of the T cell repertoire. Although previous results indicate that it exerts this function in part by promoting ectopic expression of a battery of peripheral-tissue antigens in epithelial cells of the thymic medulla, recent data argue for additional roles in negative selection of thymocytes by medullary cells. As one approach to exploring such roles, we performed computational analyses of microarray data on medullary RNA transcripts from aire-deficient versus wild-type mice, focusing on the genomic localization of aire-controlled genes. Our results highlight this molecule's transcriptional activating and silencing roles and reveal a significant degree of clustering of its target genes. On a local scale, aire-regulated clusters appeared punctate, with aire-controlled and aire-independent genes often being interspersed. This pattern suggests that aire's action may not be a simple reflection of the wide action of a chromatin remodeling enzyme. Analysis of the identity of certain of the clustered genes was evocative of aire's potential roles in antigen presentation and the coordination of intrathymic cell migration: for example, major histocompatibility complex class I and class II gene products and certain chemokine genes are targets of aire-regulated transcription.