Mechanisms for the rapid recall response mediated by memory T cells remain unknown. In this study, we present a novel, multiparameter analysis of TCR-coupled signaling and function in resting and activated naive and memory CD4 T cells, revealing a biochemical basis for immunological recall. We identify a striking elevation in expression of the proximal tyrosine kinase Zap70 in resting Ag-specif...

Objective: Regulatory T cells (Treg) have a critical role in controlling responding T cells (Tresp), thereby preventing autoimmune manifestations including those observed in adenosine deaminase (ADA) enzyme-deficient patients and mice (ADA-KO). Treg suppress various functions of Tresp such as proliferation, cytokine production and expression of activation markers, yet it is not known if Treg su...

The B-cell receptor (BCR) signaling pathway is of great importance for B-cell survival and proliferation. The BCR expressed on malignant B-CLL cells contributes to the disease pathogenesis, and its signaling pathway is currently the target of several therapeutic strategies. Although various BCR alterations have been described in B-CLL at the protein level, the mRNA expression levels of tyrosine...

OBJECTIVE Chronic lymphocytic leukemia (CLL) is a disease that shows varying clinical progression, and expression of the protein tyrosine kinase ZAP70 has been described as a very valuable prognostic factor. Patients with ZAP70 positivity are characterized by worse clinical course and significantly shorter progression-free and overall survival. In this study, intracytoplasmic interferon gamma (...

Zap70 plays a critical role in normal T cell development and T cell function. However, little is known about how perturbation of allosteric autoinhibitory mechanisms in Zap70 impacts T cell biology. Here, we analyze mice with a hypermorphic Zap70 mutation, W131A, which destabilizes the autoinhibitory conformation of Zap70, rendering the kinase in a semiactive state. W131A mutant mice with wild-...

TCR signaling plays a central role in directing developmental fates of thymocytes. Current models suggest TCR signal duration directs CD4 versus CD8 lineage development. To investigate the role of TCR signaling during positive selection directly, we switched signaling off in a cohort of selecting thymocytes and followed, in time, their subsequent fate. We did this using an inducible Zap70 trans...

The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the receptor (TCR)-mediated signaling pathway, such as lymphocyte-specific kinase (Lck), Src family kinases Fyn, and phosphorylation levels of Zeta-chain-associated kinase-70 (ZAP70). For first time, we have successfully produced CS transgenic mice which activity is suppressed. Not...

BACKGROUND AND OBJECTIVES The mutational status of the immunoglobulin heavy chain variable region genes (IGVH) is a strong indicator of prognosis in B-cell chronic lymphocytic leukaemia (CLL). Since the determination of the IGVH mutation status is very labor-intensive, alternative prognostically relevant markers would facilitate CLL diagnostics. DESIGN AND METHODS Ten genes were selected from...

We determined lymphoid enhancer-binding factor-1 (LEF1) mRNA expression in 112 chronic lymphocytic leukemia (CLL) samples and assessed correlations with the prognostic markers ZAP70 and CD38, Binet stages, the percentage of lymphocytes in the peripheral blood, and fibromodulin (FMOD) transcripts. The mean LEF1 relative expression ratios (RER) were 53.72 and 37.10 in ZAP70-positive and ZAP70-neg...

We have previously shown that a tyrosine to leucine replacement in the transmembrane region of T cell receptor (TCR)-beta results in a deficient induction of CD95-L and apoptosis upon TCR triggering in a transfected T cell line. By contrast, interleukin (IL)-2 production and the expression of CD25 and CD69 were normally induced. Since the mutation in TCR-beta also resulted in impaired associati...