9 April 2010
(Vol. 12, 2010 Mar 24) on the mechanism used by T cells of the immune system to move and interact with antigen-presenting cells (APCs) in lymph nodes.
T-cells of the immune system orchestrate the immune response to foreign antigens such as influenza virus, tumours andtransplant organs such as kidneys. They respond by recognising foreign antigens or peptides in the lymph nodes or sites of infection in the body. This leads to the proliferation of T cells and the expansion of reactive cells. The ability to respond depends on the movement of T-cells and length of time that T-cells spend attached to antigen presenting cells such as dendritic cells (DCs) that present the foreign antigen. Ligation of the antigen-receptor (also called the T-cell receptor or TCR) sends intracellular signals (termed the 'inside-out pathway') that slow T-cell motility allowing them to make stable contacts with DCs. Although essential for T cell function, the identity of the T cell receptor ‘‘inside-out’’ pathway for lymphocyte function-associated antigen 1 (LFA-1) adhesion has proved elusive.
As published this month in Immunity, the Rudd lab reports the identification of a novel ‘‘inside-out’’ pathway that is mediated by N-terminal SKAP1 (SKAP-55) domain binding to the C-terminal SARAH domain of RapL. SKAP1 and RapL are two proteins that are only found in immune cells and which send signals in cells that control adhesion and T-cell prolfieration. TcR induced Rap1-RapL complex formation and LFA-1 binding failed to occur in Skap1-/- primary T cells. SKAP1 generated a SKAP1-RapL-Rap1 complex that bound to LFA-1, whereas a RapL mutation (L224A) that abrogated SKAP1 binding without affecting MST1 disrupted component colocalisation in vesicles as well as T cell-dendritic cell (DC) conjugation. RapL expression also ‘‘slowed’’ T cell motility in D011.10 transgenic T cells in lymph nodes (LNs), an effect reversed by the L224A mutation with reduced dwell times between T cells and DCs. Overall, their ﬁndings have deﬁned a novel TCR ‘‘inside-out’’ pathway in T-cells that regulates T cell adhesion, motility, and arrest times with DCs in LNs. They are presenting trying to develop means of interfering with the N-SKAP1-C-RapL domain interaction with drugs as an immuno-suppressive treatment in transplantation and autoimmunity.
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