IL-17A Promotes Pulmonary B-1a Cell Differentiation via Induction of Blimp-1 Expression during Influenza Virus Infection

B-1 cells play a critical role in early protection during influenza infections by producing natural IgM antibodies. However, the underlying mechanisms involved in regulating this process are largely unknown. Here we found that during influenza infection pleural cavity B-1a cells rapidly infiltrated lungs, where they underwent plasmacytic differentiation with enhanced IgM production. This process was promoted by IL-17A signaling via induction of Blimp-1 expression and NF-κB activation in B-1a cells. Deficiency of IL-17A led to severely impaired B-1a-derived antibody production in the respiratory tract, resulting in a deficiency in viral clearance. Transfer of B-1a-derived natural antibodies rescued Il17a ^-/- mice from otherwise lethal infections. Together, we identify a critical function of IL-17A in promoting the plasmacytic differentiation of B-1a cells. Our findings provide new insights into the mechanisms underlying the regulation of pulmonary B-1a cell response against influenza infection.     

Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology

Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell-specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1) cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4⁺ T cells from visceral leishmaniasis (VL) patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNγ-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation.     

The dynamic expression pattern of B lymphocyte induced maturation protein-1 (Blimp-1) during mouse embryonic development

We have analyzed the spatial and temporal patterns of B lymphocyte-induced maturation protein-1 (Blimp-1) expression during mouse embryonic development. Blimp-1 expression is induced early in the anterior definitive endoderm, mesoderm of head process, and prechordal plate. In ectoderm-derived tissues at later stages, Blimp-1 expression is found in the primitive photoreceptors of neural retina, in differentiated epithelial cells of epidermis, tongue, oral and nasal cavities, and in the precursors of internal root sheaths of hair follicles. In mesoderm-derived tissues, Blimp-1 expression is observed in splanchnopleure, a subset of somatopleure-derived cells in limb buds, and myotomes of somites. Blimp-1 is also expressed in mesenchyme of developing hand plates, digits, branchial arches, nasal processes, and external genitalia. Blimp-1 is present in mesenchyme-derived chondroblasts, supporting cells of taste buds, and papilla of teeth, hair follicles and taste buds. In endoderm-derived tissues, Blimp-1 expression in the foregut region is restricted to a subset of epithelial cells at the headfold stage while expression in the endodermal epithelium of midgut and hindgut persists from the headfold stage to birth. Finally, Blimp-1 is expressed in the migrating primordial germ cells.