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The integrin α4β7 selectively regulates lymphocyte trafficking and adhesion in the gut and gut-associated lymphoid tissue (GALT). Here, we describe unexpected involvement of the tyrosine phosphatase Shp1 and the B cell lectin CD22 (Siglec-2) in the regulation of α4β7 surface expression and gut immunity. Shp1 selectively inhibited β7 endocytosis, enhancing surface α4β7 display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid-dependent manner with integrin β7 on the cell surface to target intracellular Shp1 to β7. Shp1 restrained plasma membrane β7 phosphorylation and inhibited β7 endocytosis without affecting β1 integrin. B cells with reduced Shp1 activity, lacking CD22 or expressing CD22 with mutated Shp1-binding or carbohydrate-binding domains displayed parallel reductions in surface α4β7 and in homing to GALT. Consistent with the specialized role of α4β7 in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses.

Caveolin-1 has a critical role in orchestrating the membrane organization of B cells. In its absence, signaling via the B cell antigen receptor and B cell tolerance are impaired, which results in autoimmunity.

DAP12 is a signaling adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) that pairs with receptors on myeloid cells and natural killer cells. We examine here the responses of mice lacking DAP12 to stimulation through Toll-like receptors (TLRs). Unexpectedly, DAP12-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli. Additionally, macrophages deficient in spleen tyrosine kinase (Syk), which signals downstream of DAP12, showed a phenotype identical to that of DAP12-deficient macrophages. DAP12-deficient mice were more susceptible to endotoxic shock and had enhanced resistance to infection by the intracellular bacterium Listeria monocytogenes. These data suggest that one or more DAP12-pairing receptors negatively regulate signaling through TLRs.

A key function of interferons is priming multiple cell types for enhanced activation by cytokines and inflammatory factors, including tumor necrosis factor, bacterial lipopolysaccharide and interferons themselves. Here we show that interferon-a (IFN-α)-induced activation of the transcriptional activator STAT1 and inflammatory STAT1 target genes was enhanced in IFN-c-primed macrophages. Enhanced IFN-a signaling and proinflammatory function were dependent on the tyrosine kinase Syk and on adaptor proteins that activate Syk through immunoreceptor tyrosine activation motifs. Increased STAT1 expression contributed to enhanced IFN-α-induced STAT1 activation in primed macrophages. These results identify a mechanism by which crosstalk between cytokine and immune cell-specific immunoreceptor tyrosine activation motif-dependent signaling pathways regulates macrophage responses to IFN-α. [ABSTRACT FROM AUTHOR]

The nature of signals that govern the development of immunoglobulin heavy chain-dependent B cells is largely unknown. Using mice deficient for the B cell-expressed Src-family protein tyrosine kinases (SFKs) BIk, Fyn and Lyn, we show an essential role of these kinases in pre-B cell receptor (pre-BCR)mediated NF-κB activation and B cell development. This signaling defect is SFK specific, as a deficiency in Syk, which controls pre-B cell development, does not affect NF-κB induction. Impaired NF-κB induction was overcome by the activation of protein kinase C (PKC)-λ, thus suggesting the involvement of PKC-λ in pre-BCR-mediated SFK-dependent activation of NF-κB. Our data show the existence of a functionally distinct SFK signaling module responsible for pre-BCR-mediated NF-κB activation and B cell development. [ABSTRACT FROM AUTHOR]

The integrin α 4 β 7 selectively regulates lymphocyte trafficking and adhesion in the gut and gut-associated lymphoid tissue (GALT). Here, we describe unexpected involvement of the tyrosine phosphatase Shp1 and the B cell lectin CD22 (Siglec-2) in the regulation of α 4 β 7 surface expression and gut immunity. Shp1 selectively inhibited β 7 endocytosis, enhancing surface α 4 β 7 display and lymphocyte homing to GALT. In B cells, CD22 associated in a sialic acid-dependent manner with integrin β 7 on the cell surface to target intracellular Shp1 to β 7 . Shp1 restrained plasma membrane β 7 phosphorylation and inhibited β 7 endocytosis without affecting β 1 integrin. B cells with reduced Shp1 activity, lacking CD22 or expressing CD22 with mutated Shp1-binding or carbohydrate-binding domains displayed parallel reductions in surface α 4 β 7 and in homing to GALT. Consistent with the specialized role of α 4 β 7 in intestinal immunity, CD22 deficiency selectively inhibited intestinal antibody and pathogen responses.

The nature of signals that govern the development of immunoglobulin heavy chain-dependent B cells is largely unknown. Using mice deficient for the B cell-expressed Src-family protein tyrosine kinases (SFKs) Blk, Fyn and Lyn, we show an essential role of these kinases in pre-B cell receptor (pre-BCR)- mediated NF-kappaB activation and B cell development. This signaling defect is SFK specific, as a deficiency in Syk, which controls pre-B cell development, does not affect NF-kappaB induction. Impaired NF-kappaB induction was overcome by the activation of protein kinase C (PKC)-lambda, thus suggesting the involvement of PKC-lambda in pre-BCR-mediated SFK-dependent activation of NF-kappaB. Our data show the existence of a functionally distinct SFK signaling module responsible for pre-BCR-mediated NF-kappaB activation and B cell development.