In This Issue

β-2 adrenergic receptor (β₂AR), a norepinephrine receptor expressed on B cells, participates in pathological pathways in allergy and asthma and regulates IgE production via mechanisms that have yet to be fully elucidated. Stimulation of β₂AR increases B cell expression of CD23, a surface IgE receptor that can be cleaved by ADAM10 to a soluble form (sCD23), which positively regulates IgE production. CD23 is also expressed on B cell exosomes, cell-derived cholesterol-rich vesicles capable of regulating immune cell activity in a paracrine or autocrine fashion, but whether the release of these vesicles plays a role in IgE production is unknown. To determine the mechanisms linking signaling events proximal to β₂AR stimulation to distal intermediates that induce increased sCD23 and IgE production, Padro et al. (p. 5383) primed B cells with CD40L and IL-4 and then stimulated them with the β₂AR agonist terbutaline. They found terbutaline-stimulated B cells increased gene expression and protein levels of ADAM10, as well as protein levels of CD23, in a PKA- and p38 MAPK-dependent manner. B cell surface expression of CD23 did not increase, but exosomes released from B cells expressed heightened levels of CD23 and ADAM10, indicating that perhaps these molecules are allocated to exosomes to mediate β₂AR-enhancing effects on IgE secretion. Transfer of exosomes from β₂AR agonist-stimulated wildtype, but not β₂AR^−/−, B cells to primed B cell cultures induced increased Ab secretion by IgE-producing B cells without altering the overall number of B cells producing IgE, indicating that these events are β₂AR-dependent. These results suggest that B cell β₂AR stimulation promotes increased CD23 and ADAM10 expression followed by shuttling of these proteins to IgE-enhancing exosomes.

The contraction phase of the T cell response to lymphocytic choriomeningitis virus (LCMV) infection is marked by a rapid decline of antiviral CD8⁺ T cells to stable levels within 1–2 wk. In contrast, virus-specific CD4⁺ T cells gradually decline and only reach homeostatic levels 1–2 mo following viral clearance. Using LCMV-Armstrong, which generates a robust CD8⁺ T cell response in wild-type mice that culminates in the elimination of infectious virus and viral RNA within ∼1 wk, Misumi et al. (p. 5655) compared the impact of viral Ag persistence following infection on contraction phase kinetics of CD8⁺ and CD4⁺ T cell populations. Transfer of naive, LCMV-specific, transgenic CD8⁺ T cells into either naive, LCMV-infected, or LCMV-immune mice indicated that donor CD8⁺ T cells did not divide during the contraction or memory phase after acute infection, suggesting that residual MHC I–restricted viral Ag was insufficient to elicit division. Similar experiments with CD4⁺ T cells demonstrated that although de novo viral protein synthesis is absent, persistent viral Ag stimulated Ag-specific CD4⁺ T cells to undergo cell division during the contraction and early memory phases. Quantification of CD4⁺ T cell division following LCMV infection showed that 74% of naive T cells but only 1% of Ag-experienced T cells divided in the contraction phase, suggesting that memory T cells do not proliferate in response to residual MHC II–restricted Ag. These data highlight the different kinetics of the contraction phase between CD8⁺ and CD4⁺ T cells and indicate that residual viral Ag recruits naive, but not Ag-experienced, CD4⁺ T cells following acute viral infection, thereby maintaining the diversity of the T cell response during its contraction phase.

The pathological and regulatory mechanisms involved in follicular bronchiolitis (FB), a condition in which lymphoid follicles form in the BALT of patients with underlying chronic autoimmune lung inflammation, are largely unknown. To dissect the etiology and regulation of FB, Schmitt et al. (p. 5460) developed a transgenic (Tg) FB mouse model expressing the mouse hemoglobin (Hb) immunodominant epitope Hb (64–76) under the control of the Clara cell secretory protein promoter to restrict expression of this peptide primarily to the respiratory bronchioles. Crossing these mice to N3.L2 TCR Tg mice, which harbor CD4⁺ T cells specific for Hb (64–76), yielded “bigenic” mice whose lungs exhibited lymphocytic peribronchiolar infiltrates and bronchiolar inflammation characteristic of FB. Significantly increased numbers of Hb-specific CD4⁺ T cells producing IFN-γ or IL-17 infiltrated the lungs of bigenic mice compared with N3.L2 controls. IL-17– or IFN-γ–deficient bigenic mouse lungs displayed similar pathology to bigenic control lungs, indicating either cytokine is sufficient to induce disease. Hb-specific regulatory T cells (Tregs) also accumulated in bigenic mouse lungs and were integral in limiting the spread and severity of FB; bigenic mice expressing diphtheria toxin (DT) receptor driven by the Foxp3 promoter and treated with DT had reduced numbers of Tregs in the lungs and increased lung pathology that resulted in death. These results suggest Tregs limit the severity of pathology caused by FB and are involved in a fundamental mechanism that prevents disease progression to a critical and life-threatening state.

A desirable and difficult goal of allogeneic hematopoietic cell transplantation is to prevent graft-versus-host disease (GVHD) while maintaining graft-versus-tumor activity. Total lymphoid irradiation and anti-thymocyte globulin (TLI/ATG) in patients and TLI with anti-thymocyte serum (ATS) in MHC mismatched animal models successfully demonstrate protection against GVHD without impairing tumor eradication. Previous studies have shown that this desirable effect is driven by recipient Th2-polarized invariant NK T (iNKT) cells that secrete IL-4 and drive naturally occurring regulatory CD4⁺CD25⁺Foxp3⁺ (nTreg) cells to dampen donor effector CD8⁺ T cell GVHD responses. To further delineate this mechanism, van der Merwe et al. (p. 5764) used an allogeneic bone marrow transplantation (BMT) model in which wild-type (wt) C57BL/6 (H-2^b) bone marrow was transplanted into wt BALB/c (H-2^d) recipients followed by TLI/ATS (Th2-polarizing) or total body irradiation (TBI)+ATS (Th1-polarizing) treatment. TLI/ATS, but not TBI+ATS conditioning, significantly reduced donor CD8⁺ T cells and protected transplant recipient mice from GVHD. Similar results in experiments with BMT from STAT6-deficient (STAT6^−/−) donors suggested that the nTreg-expanding effects of IL-4 were indirect and dependent on recipient CD11b⁺Gr-1^lowCD11c⁺ cells, which had dendritic cell morphology and monocyte lineage markers. This Gr-1^lowCD11c⁺ population expressed MHC I, MHC II, CD1d, and IL-4Rα, and secreted iNOS and TNF-α, but not Th2 cytokines, following TLR4 stimulation. Ablation of STAT6 or iNKT cells (Ja18^−/− mice) led to a significant reduction in Gr-1^lowCD11c⁺ cells and GVHD protection. Adoptive transfer of Gr-1^lowCD11c⁺ cells into STAT6^−/− and Ja18^−/− mice reversed this reduction, suggesting that the expansion of Gr-1^lowCD11c⁺ cells was dependent on iNKT-derived IL-4 production. Gr-1^lowCD11c⁺ cells, in turn, mediated a contact- and programmed death ligand 1 (PD-L1)-dependent induction of nTregs. These data suggest a mechanism by which iNKT-derived IL-4 promotes a population of myeloid-derived immunomodulatory cells, which in turn expand nTregs through PD-L1, thus preventing GVHD in allogeneic transplantation.