Immune response - IL-7 signaling in B lymphocytes

IL-7 signaling in B lymphocytes

Interleukin 7 (IL-7) is an essential cytokine for the development and maintenance of B lymphocytes. Interleukin 7 receptor (IL-7 receptor), regulates lymphocyte survival, proliferation and differentiation [1], [2]. IL-7 receptor consists of two components, IL-7 receptor alpha chain (IL7RA) and a common gamma chain, Interleukin 2 receptor gamma (IL-2R gamma chain) [3].

IL-7 ligation to IL7RA results in its dimerization with IL-2R gamma chain and IL-7 receptor activation, which leads to subsequent tyrosine phosphorylation and activation of Janus kinases 1 and 3 (JAK1 and JAK3) [4], [5] and Src family tyrosine kinases FYN oncogene related to SRC (Fyn) [5], [6], and v-Yes-1 Yamaguchi sarcoma viral related oncogene homolog (Lyn) [7].

Active JAK1 and JAK3 induce phosphorylation of Signal transducers and activators of transcription 1, 3, and 5 (STAT1, STAT3 and STAT5) and their nuclear translocation [8], [9], [10]. STAT5 promotes transcription of target genes, expressing BCL2-like 1 (Bcl-XL), Pim-1 oncogene (Pim-1), and Cyclin D2. Bcl-XL leads to B-cells survival. Pim-1 and Cyclin D2 leads to cell proliferation [9].

In addition, IL-7 stimulates mitogen activated protein kinase ERK activation in B cells [11], [12], possibly, via JAK1/ Growth factor receptor-bound protein 2 (GRB2) / Son of sevenless homologues (SOS)/ V-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Harvey rat sarcoma viral oncogene homolog (H-Ras)/ Mitogen-activated protein kinase kinases 1 and 2 (MEK1 (MAP2K1) and MEK2 (MAP2K2) [13], [14]. IL-7-induced ERK stimulates cell proliferation [11], [12]

Phosphorylated JAKs and Src kinases induce Phosphoinositide-3-kinase regulatory subunit 1alpha (PI3K reg class IA (p85-alpha)), which activates Phosphoinositide-3-kinase catalytic alpha polypeptide (PI3K cat class IA (p 110-alpha)) that leads to Phosphatidylinositol(3,4,5) triphosphate (PtdIns(3,4,5)P3) conversion from PtdIns(4,5)P2. PtdIns(3,4,5)P3 in turn induces Akt(PKB) and 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)) activation that promotes lymphocytes proliferation.

IL-7 stimulates V(D)J recombination of Immunoglobulin H (Igh) in B 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 [15]. IL-7 receptor signaling cause up regulation of the transcription factors Early B-cell factor 1 (EBF) in STAT5-, Paired box 5 (PAX5) and Transcription factor 3 (E2A)-dependent manner [16], [17], [18]. STAT5 functions at a distinct step in distal Immunoglobulin H (Igh) recombination in relation to Pax5, EBF and Oct-1 [19]. E2A stimulate expression of N-Myc activating B cell proliferation [20].

In addition, Akt(PKB) activation serves for Forkhead boxes O1 (FKHR) negative control. It leads to inhibition of FKHR-dependent transcription Recombination activating gene 1 and 2 (RAG1 and RAG2) stimulating B cell differentiation. The RAG1/ RAG2 dimer recognizes the synapsis formed by the recognition motifs and initiates the cleavage step of V(D)J recombination [21].

After IL-7 promotes immunoglobulin gene rearrangement, pre-B cell receptor (pre-BCR) decreases expression of the IL7RA and responsiveness of pre-B cells to IL-7 signals [1], [22].

References:

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