TEC FAMILY KINASES AND SIGNALING PATHWAYS IN IMMUNE CELLS

Members of the Tec kinase family (Bmx, Btk, Itk, Rlk and Tec) constitute the second largest family of non-receptor tyrosine kinases and are preferentially expressed in the hematopoietic system. A large number of studies have shown important roles for these kinases in the lymphoid system. Furthermore, mice with combinatorial deletions of Tec family kinases revealed both unique and redundant functions in B cells (Tec, Btk) and T cells (Rlk, Itk). In ongoing studies we are investigating in more detail the role of Tec family kinases in T cells.

Although Tec family kinase members are also expressed in myeloid cells, little is known about their function in this lineage. To learn more about the role of Tec kinases in myeloid cells, we are analyzing the function of primary myeloid cell lineages such as mast cells and monocytes/macrophages lacking single and/or multiple Tec kinase family members. Our studies will contribute to a better understanding of the immunomodulatory role of Tec kinases in cells of the immune system, and may on the long-term also help to indicate strategies for potential therapeutic intervention.


The role of Tec family kinases in T cells

Itk and the GDP/GTP guanine exchange factor Vav1 act in similar T cell activation pathways. Both molecules interact with members of the Cbl family of E3 ubiquitin ligases, and signaling defects in Vav1-/- T cells are rescued upon deletion of Cbl-b. We investigated the relation between Itk and Cbl-b or Vav1 by generating Itk/Cbl-b and Itk/Vav1 double-deficient mice. We could show that Itk and Vav1 act mechanistically similar in peripheral T cells, since the defects in Itk-/- T cells, like in Vav1-/- T cells, are rescued if cells are released from the negative regulation mediated by Cbl-b. Moreover, our studies revealed that the combined activity of Itk and Vav1 is required for proper T cell development and the generation of the peripheral T cell pool.

Moreover, in collaboration with Edvard Smith (Karolinska Institute, Sweden) we recently characterized the transcriptome of Itk-deficient T-cells, including CD4+ and CD8+ subsets, using Affymetrix microarrays, and provided a general overview about the global transcriptional changes in the absence of Itk. Currently, differentially expressed genes are analyzed.


The role of Tec family kinases in myeloid cells

We identified important processes in myeloid cells that are regulated by Tec kinases. We demonstrated that Tec is a crucial regulator of mast cell function, since Tec-deficient mast cells have an impaired effector function upon Fc-epsilonRI stimulation. In addition, we showed that Tec and Btk regulate M-CSFR signaling-induced macrophage survival. Currently, we investigate in detail how macrophage function is regulated by Tec family kinases.



The research in the field of Tec family kinaes is supported by the FWF Doktoratskolleg "Inflammation and Immunity" (W1212).


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