Role of inositol poly-phosphatases and their targets in T cell biology

Abstract

T lymphocytes play a critical role in host defense in all anatomical sites including mucosal surfaces. This not only includes the effector arm of the immune system, but also regulation of immune responses in order to prevent autoimmunity. Genetic targeting of PI3K isoforms suggests that generation of PI(3,4,5)P3 by PI3K plays a critical role in promoting effector T cell responses. Consequently, the 5'- and 3'-inositol poly-phosphatases SHIP1, SHIP2, and phosphatase and tensin homolog capable of targeting PI(3,4,5)P3 are potential genetic determinants of T cell effector functions in vivo. In addition, the 5'-inositol poly-phosphatases SHIP1 and 2 can shunt PI(3,4,5)P3 to the rare but potent signaling phosphoinositide species PI(3,4)P2 and thus these SHIP1/2, and the INPP4A/B enzymes that deplete PI(3,4)P2 may have precise roles in T cell biology to amplify or inhibit effectors of PI3K signaling that are selectively recruited to and activated by PI(3,4)P2. Here we summarize recent genetic and chemical evidence that indicates the inositol poly-phosphatases have important roles in both the effector and regulatory functions of the T cell compartment. In addition, we will discuss future genetic studies that might be undertaken to further elaborate the role of these enzymes in T cell biology as well as potential pharmaceutical manipulation of these enzymes for therapeutic purposes in disease settings where T cell function is a key in vivo target.

Keywords: INPP4; PI3K; PTEN; SHIP1; SHIP2; T cells; T lymphocytes; adoptive T cell transfer.

Figure 1

Phosphoinositide signaling and its regulation by phosphatases. PI3K converts PI(4,5)P₂ to a key secondary messenger PI(3,4,5)P_3. Phosphatases like PTEN and SHIP1/2 regulate cellular levels of PI(3,4,5)P₃ by hydrolyzing it to PI(4,5)P₂ and PI (3,4)P₂ respectively. PLCγ converts PI(4,5)P₂ to IP₃ and DAG. IP₃ a soluble inositol phosphate is required for Ca²⁺ mobilization while DAG can activate the Ras-Raf-ERK1/2 pathway. IP₃ 3-Kinases convert IP₃ to IP₄, another important soluble inositol poly-phosphate that either positively or negatively regulates the binding of PI(3,4,5)P₃ to PH-domain containing proteins. The SHIP1/2 product PI(3,4)P2 is hydrolyzed by INPP4A/B into PI(3)P by removal of the phosphate at the 4-position of the inositol ring. PI(3,4,5)P₃ and/or PI(3,4)P₂ enable recruitment to the plasma membrane of several PH-domain containing proteins including PDK1, AKT, BTK, ITK, and thus regulate pivotal cellular processes including activation, proliferation, and survival. PH-domain containing adaptor proteins (GABs, SKAPs, Bam32, and TAPP) can also bind to phosphoinositides and regulate cell signaling (indicated as green boxes). AKT, Protein Kinase B; PDK1, phosphoinositide-dependent kinase-1, PLCγ phospholipase Cγ; ITK, IL-2-inducible T cell kinase) and BTK, Bruton agammaglobulinemia tyrosine kinase.

Figure 2

Inositol phosphatases in T cell biology. Upon TCR stimulation PI3K is activated and recruited to the membrane through its SH2 domain where it phosphorylates its substrate PI(4,5)P₂ converting it to PI(3,4,5)P₃. PI(3,4,5)P₃ is bound by PH-domain containing proteins such as AKT, PDK1, BTK, ITK, Vav, and PLCγ triggering secondary signaling cascades and thus T cell activation, proliferation, survival, and cytokine production. PI3K signaling is tightly regulated by inositol phosphatases. PI(3,4,5)P₃ is a substrate for three inositol phosphatases, SHIP1/2 and PTEN which hydrolyze PI(3,4,5)P₃ to PI(3,4,)P₂ and PI(4,5)P₂, respectively. By limiting the cellular pool of the second messenger PI(3,4,5)P₃, PTEN and SHIP play important functions in T cell development, proliferation, and activation. The SHIP1 product PI(3,4)P₂ which can also recruit and activate AKT is dephosphorylated by INPP4. However the role of these 4-phosphatases in T cell biology has yet to be determined. AKT, Protein Kinase B; PDK1, phosphoinositide-dependent kinase-1, PLCγ phospholipase Cγ; ITK, IL-2-inducible T cell kinase) and BTK, Bruton agammaglobulinemia tyrosine kinase.