Tec kinase Itk in γδT cells is pivotal for controlling IgE production in vivo

Abstract

T cell development ͉ T cell differentiation ͉ T cell signaling T he Tec family tyrosine kinase Itk is important for signaling downstream of the T cell receptor (1). In particular, Itkdeficient T cells have defects in phospholipase C-␥ (PLC-␥) phosphorylation, calcium mobilization, mitogen-activated protein kinase (MAP kinase) activation, and AP-1 and nuclear factor of activated T cells (NFAT) activation after T cell receptor (TCR) stimulation. Itk is also critical for conventional ␣␤ T cell development, selection, and function. Of particular importance, Itk signaling regulates CD4 ϩ T helper cell differentiation, playing a key role in the development of Th2 responses (2). Based on this welldocumented defect of Itk Ϫ/Ϫ mice in generating Th2 effector responses and cytokine production, it was surprising to discover that these mice had spontaneously elevated levels of serum IgE (3, 4), as B cell isotype switching to IgE is highly dependent on Th2 cytokines IL-4 and IL-13 (5). As our previous studies had indicated that Itk Ϫ/Ϫ ␣␤ TCR ϩ NKT cells (referred to as ␣␤ NKT cells) were also highly defective in producing effector cytokines such as IL-4 (6), we considered the possibility that ␥␦ TCR ϩ NKT cells were the major source of Th2 cytokines in Itk Ϫ/Ϫ mice.The ␥␦ T cells are a highly conserved subset of T cells that constitutes 1-5% of the lymphocytes in the blood and peripheral organs of mice but can account for up to 50% of the lymphocytes in the mucosal epithelia. As with other subsets of ''innate'' T cells, ␥␦ T cells express memory cell surface markers (7), and are capable of rapidly secreting effector cytokines (8). Among the many functions attributed to ␥␦ T cells, a great deal of recent interest has focused on their ability to modulate adaptive immune responses, specifically the humoral response (9).A variety of studies have indicated that ␥␦ T cells are able to provide help for B cell responses. Initial studies performed in mice lacking ␣␤ T cells showed that B cell expansion, differentiation, and secretion of 'T-dependent' antibody isotypes, IgE, and IgG 1 , were all intact in these mice (10). Furthermore, TCR␤ Ϫ/Ϫ mice challenged repeatedly with parasitic infections could produce germinal centers and generate increased antibody production (11). Using a model of pulmonary allergic inflammation, decreased production of IgE and IgG 1 was seen in mice lacking ␥␦ T cells compared with WT mice (12). The ␥␦ T cells have also been shown to directly induce germinal center formation and Ig hypermutation (13). Interestingly, even though the ␥␦ T cells expressing CD4 account for only 5-10% of all ␥␦ cells, it is this subset that appears to be responsible for inducing germinal centers (14). Human ␥␦ T cells have also been found in germinal centers; these cells were found to up-regulate B cell costimulatory molecules such as CD40L, OX40, CD70, and inducible costimulatory molecule (ICOS) in response to TCR stimulation (15, 16). Together, these data indicate that ␥␦ T cells can promote, either directly or indirectly, th...

A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice

“…2B). In contrast to recent studies, which reported an expansion of NKT cells expressing a γ/δ TCR in mice with mutations within proximal TCR signaling molecules or a lack of the transcription factor Id3 [55][56][57][58][59][60][61], we did not observe an accumulation of this rare NKT cell subset in slp-76 ace/ace mice (data not shown). Thus, besides NK cells [53] the slp-76-mutation specifically affects α/β-TCR + iNKT cells.…”

The Role of Tyrosine Kinases in the Pathogenesis and Treatment of Lung Disease

“…Consistent with this, Itk deficient mice have reduced antigenspecific T cell recruitment to the lung, decreased IL-5 and IL-13 production, reduced antigen-mediated T cell proliferative responses, as well as attenuated eosinophil infiltration and mucus production (Mueller & August, 2003). Reduced airway inflammation in Itk knockout mice is caused by an increase in  T cells that attenuate mast cell responses (Felices, Yin, Kosaka, Kang, & Berg, 2009;Qi et al, 2009). Itk deficient mice also have reduced AHR (Ferrara, Mueller, Sahu, Ben-Jebria, & August, 2006).…”

TCR-inducible PLZF transcription factor required for innate phenotype of a subset of γδ T cells with restricted TCR diversity

“…These V␥1ϩV␦6.3/V␦6.4ϩ cells were previously reported to share phenotypic and functional properties with NKT cells (15)(16)(17)(18). A recent study reported that their numbers are increased in ItkϪ/Ϫ mice and that total ␥␦ T cells from these mice express high levels of PLZF mRNA (31). Our results demonstrate that at least some of the NKT-like properties of these cells are a part of a common program that requires the transcription factor PLZF for its execution.…”