Immune response - IL-7 signaling in T lymphocytes

IL-7 signaling in T lymphocytes

Interleukin-7 (IL-7) is an essential cytokine for proliferation, maintenance and survival of T-lymphocytes [1]. IL-7 receptor activates pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation [2].

IL-7 receptor consists of the IL-7 receptor alpha chain (IL7RA) and the common cytokine gamma chain (IL-2R gamma chain) [1]. IL-7 ligation to the IL-7 receptor stimulates the trans-phosphorylation of receptor associated Janus kinases 1 and 3 (JAK1 and JAK3), which in turn phosphorylate tyrosine residues on the receptors themselves [3], [4], [5].

IL-7 receptor serves as docking sites for SH2 domain proteins including the Signal transducers and activators of transcription family of transcription factors (STAT1, STAT3, STAT5 and STAT6) which are activated by JAK-mediated phosphorylation [6], [7]. STAT5 promotes transcription of B-cell CLL/lymphoma 2 (Bcl-2) stimulating cell survival [8]. STAT5 promotes transcription of Suppressor of cytokine signaling 1 (SOCS1) inducing negative feed-back on IL-7 signaling [9], [10].

IL-7 receptor induces JAKs/ PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2)) cascade that participates in activation of T cell survival [5].

Activated IL-7 receptor stimulates Phosphatidylinositol 3-kinase (PI3K)/ V-akt murine thymoma viral oncogene (AKT/PKB) cascade via JAKs/ Insulin receptor substrates 1 and 2 (IRS-1, IRS-2) [11], [12] and/or Src family kinases FYN oncogene related to SRC (Fyn) and Lymphocyte-specific protein tyrosine kinase (Lck) [4], [13]. Activated PI3K induces conversion from Phosphatidyl-4,5-inositol bisphosphate (PtdIns(4,5)P2) to Phosphatidyl-3,4,5-inositol triphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 in turn induces AKT/PKB and 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)) activation that promotes T lymphocytes proliferation and survival [14], [15].

AKT/PKB complex induces Solute carrier family 2 member 1 (GLUT1) activation inhibition of transcriptional factor Forkhead box O3 (FOXO3A). GLUT1 stimulates Glucose uptake thus promoting cell survival [16].

IL-7 stimulates V(D)J recombination of T-cell receptor gamma chain (TCR gamma locus) in T cells. V(D)J recombination is assemblage of mature genes encoding the component chains of TCR and immunoglobulin proteins from germ-line arrays of variable (V), diversity (D), and joining (J) gene segments during lymphoid development [17], [18]. STAT5 plays a key role in synthesis and V(D)J recombination of TCR gamma locus with participation of histone acetylases p300 and CBP [19]. It is possibly, that AKT/PKB-dependent inhibition Forkhead box O1 (FKHR) stimulates Recombination activating gene 1 and 2 (RAG1 and RAG2) transcription, thus inducing V(D)J recombination of TCR gamma locus. The RAG1/ RAG2 dimer recognizes the synapsis formed by the recognition motifs and initiates the cleavage step of V(D)J recombination [10], [17], [20].

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