The molecular mechanisms that govern thymocyte development and maturation are incompletely understood. The P21-activated kinase 2 (Pak2) is an effector for the Rho family GTPases Rac and Cdc42 that regulate actin cytoskeletal remodeling, but its role in the immune system remains poorly understood. In this study, we show that T-cell specific deletion of Pak2 gene in mice resulted in severe T cell lymphopenia accompanied by marked defects in development, maturation, and egress of thymocytes. Pak2 was required for pre-TCR β-selection and positive selection. Surprisingly, Pak2 deficiency in CD4 single positive thymocytes prevented functional maturation and reduced expression of S1P1 and KLF2. Mechanistically, Pak2 is required for actin cytoskeletal remodeling triggered by TCR. Failure to induce proper actin cytoskeletal remodeling impaired PLCγ1 and Erk1/2 signaling in the absence of Pak2, uncovering the critical function of Pak2 as an essential regulator that governs the actin cytoskeleton-dependent signaling to ensure normal thymocyte development and maturation.
T cells are a key element of the immune system. There are many different types of T cells, and they all have their origins in hematopoietic stem cells that are found in the bone marrow. These stem cells leave the bone marrow and circulate in the body until they reach an organ called the thymus, where they become early thymic progenitor cells. These progenitor cells then undergo a process called differentiation to become specific types of T cells, which mature in the thymus before moving to the blood. Although various molecules and mechanisms are known to be involved in the development of T cells, many details of this process are not understood.
One group of molecules that has been implicated in the differentiation of T cells is the p21-activated kinases. Kinases are proteins that activate or deactivate other proteins by adding phosphate groups to specific amino acids. Pak2 adds phosphorylate groups to various proteins that are involved in the reorganization of an important structure inside the cell called the cytoskeleton.
A kinase called Pak2 has an important role in the reorganization of the cytoskeleton, and since this reorganization is involved in almost all aspects of T cell biology, it seems plausible that Pak2 is also involved in the development of T cells. However, it has not been possible to test this idea because deleting the gene for Pak2 in mice results in their death.
Now, Phee et al. have overcome this problem by performing experiments in which the gene for Pak2 was only deleted in T cells. These mice had significantly fewer mature T cells than healthy mice. In particular, the absence of Pak2 in thymocytes (the cells that become T cells) prevented them from maturing into T cells, and also prevented them from producing a receptor protein that is needed for mature T cells to leave the thymus. This work implies that disruption of the Pak2-mediated signaling pathway that regulates the cytoskeleton may weaken the immune system in humans.