STAT6 is required for the regulation of IL-4-induced cytoskeletal events in B cells

Abstract

During lymphocyte activation, changes in cell morphology are commonly observed. This reflects cell functions important for the regulation of immune responses such as cell adhesion or cell migration. Notably, IL-4 has been shown to induce adhesion and locomotion in B cells, and we have recently described that IL-4 causes dramatic changes in B cell morphology. Thus, such B cells spread with dendritic cell protrusions and produce microvilli-like structures. The molecular mechanisms by which IL-4 induces these complex changes are currently unknown. Two signal transduction pathways are well described for IL-4, i.e. one involving insulin receptor substrate (IRS)-2 and a Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway mediated by STAT6. In this study we therefore used B cells from STAT6-deficient mice to address the question of a possible STAT6 dependence in IL-4-induced morphology changes. By light and electron microscopy, cell spreading and polarization were found to be severely impaired and microvilli formation was reduced. In contrast, only mild impairment was observed in cell adhesion in B cells from STAT6-deficient mice. Our results show that adhesion can be induced in the absence of STAT6. However, expression of STAT6 is necessary for optimal responses in both cell adhesion and microvilli induction. STAT6 is also essential to allow an IL-4-dependent spreading or polarization response. A possible interpretation of our results is that STAT6-dependent expression of a specific gene or genes is required for IL-4 to affect changes in B cell morphology.

Cdc42, Rac1, and the Wiskott-Aldrich syndrome protein are involved in the cytoskeletal regulation of B lymphocytes

“…IL-4-induced morphology is at least partly mediated by the signal transducer and activator of transcription Stat-6 protein because Stat-6 Ϫ/Ϫ B cells are deficient in the induction of motile and spread cells and also in microvilli formation. 9 We are investigating a possible link between Stat-6-activated genes and WASP-dependent signaling pathways.…”

“…Thymus-independent stimulus lipopolysaccharide (LPS) from gram-negative bacteria, and even more pronounced IL-4 and agonistic anti-CD40 antibodies (anti-CD40 monoclonal antibody [mAb]), mimicking the CD40 ligand, stimulate B lymphocytes to acquire a motile shape. [6][7][8][9] It has been shown that anti-CD40 or LPS plus IL-4, but not LPS alone, induces the formation of dendritic protrusions when B cells are cultured on immobilized antibodies directed to B-cell surface determinants. 10,11 LPS plus IL-4 12 or anti-CD40 13 induces homotypic B-cell aggregates that are tight and spherical, whereas LPS-induced aggregates are loose and irregularly shaped.…”

“…14 The induction of spread cells and tight aggregates are correlated with an increase in number and length of villous structures on the B-cell surface. 9 Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency disorder caused by mutations in the gene encoding the WAS protein (WASP). Lymphocytes from patients with WAS have aberrant formation of microvilli.…”

“…IL-4-induced morphology is at least partly mediated by the signal transducer and activator of transcription Stat-6 protein because Stat-6 Ϫ/Ϫ B cells are deficient in the induction of motile and spread cells and also in microvilli formation. 9 We are investigating a possible link between Stat-6-activated genes and WASP-dependent signaling pathways.As judged by scanning electron microscopy, nonactivated human blood lymphocytes have fine villous projections. WAS blood lymphocytes have fewer microvilli, and those expressed are usually abnormally shaped in that they are short and blunted.…”

Adjuvant formulations possess differing efficacy in the potentiation of antibody and cell mediated responses to a human malaria vaccine under selective immune genes knockout environment

“…STAT6, as an additional approach to the cytokine KO studies. The STAT6 transcription factor has been shown to play critical roles in the development of TH2 responses [19,20], particularly in a number of IL-4 mediated immune responses, including Ig gene transcriptions and switch recombination [21][22][23], B cell differentiation, maturation and survival [24][25][26]. Other studies have also shown some of IL-4's positive effects on B cells are driven independent of STAT6 [27].…”