Cutting Edge: Drebrin-Regulated Actin Dynamics Regulate IgE-Dependent Mast Cell Activation and Allergic Responses.

Mast cells play critical roles in allergic responses. Calcium signaling controls the function of these cells, and a role for actin in regulating calcium influx into cells has been suggested. We have previously identified the actin reorganizing protein Drebrin as a target of the immunosuppressant 3,5-bistrifluoromethyl pyrazole, which inhibits calcium influx into cells. In this study, we show that Drebrin(-/-) mice exhibit reduced IgE-mediated histamine release and passive systemic anaphylaxis, and Drebrin(-/-) mast cells also exhibit defects in FcεRI-mediated degranulation. Drebrin(-/-) mast cells exhibit defects in actin cytoskeleton organization and calcium responses downstream of the FcεRI, and agents that relieve actin reorganization rescue mast cell FcεRI-induced degranulation. Our results indicate that Drebrin regulates the actin cytoskeleton and calcium responses in mast cells, thus regulating mast cell function in vivo.

ITK independent development of Th17 responses during hypersensitivity pneumonitis driven lung inflammation.

T helper 17 (Th17) cells develop in response to T cell receptor signals (TCR) in the presence of specific environments, and produce the inflammatory cytokine IL17A. These cells have been implicated in a number of inflammatory diseases and represent a potential target for ameliorating such diseases. The kinase ITK, a critical regulator of TCR signals, has been shown to be required for the development of Th17 cells. However, we show here that lung inflammation induced by Saccharopolyspora rectivirgula (SR) induced Hypersensitivity pneumonitis (SR-HP) results in a neutrophil independent, and ITK independent Th17 responses, although ITK signals are required for γδ T cell production of IL17A. Transcriptomic analysis of resultant ITK independent Th17 cells suggest that the SR-HP-induced extrinsic inflammatory signals may override intrinsic T cell signals downstream of ITK to rescue Th17 responses in the absence of ITK. These findings suggest that the ability to pharmaceutically target ITK to suppress Th17 responses may be dependent on the type of inflammation.

Beyond Type 1 Regulatory T Cells: Co-expression of LAG3 and CD49b in IL-10-Producing T Cell Lineages.

Type 1 regulatory CD4+ T (Tr1) cells express high levels of the immunosuppressive cytokine IL-10 but not the master transcription factor Foxp3, and can suppress inflammation and promote immune tolerance. In order to identify and obtain viable Tr1 cells for research and clinical applications, co-expression of CD49b and LAG3 has been proposed as a unique surface signature for both human and mouse Tr1 cells. However, recent studies have revealed that this pattern of co-expression is dependent on the stimulating conditions and the differentiation stage of the CD4+ T cells. Here, using an IL-10GFP/Foxp3RFP dual reporter transgenic murine model, we demonstrate that co-expression of CD49b and LAG3 is not restricted to the Foxp3- Tr1 cells, but is also observed in Foxp3+ T regulatory (Treg) cells and CD8+ T cells that produce IL-10. Our data indicate that IL-10-producing Tr1 cells, Treg cells and CD8+ T cells are all capable of co-expressing LAG3 and CD49b in vitro following differentiation under IL-10-inducing conditions, and in vivo following pathogenic insult or infection in the pulmonary mucosa. Our findings urge caution in the use of LAG3/CD49b co-expression as sole markers to identify Tr1 cells, since it may mark IL-10-producing T cell lineages more broadly, including the Foxp3- Tr1 cells, Foxp3+ Treg cells, and CD8+ T cells.