IRF2BP2 transcriptional repressor restrains naive CD4 T cell activation and clonal expansion induced by TCR triggering

Abstract

CD4 T cell activation and differentiation mechanisms constitute a complex and intricate signaling network involving several regulatory proteins. IRF2BP2 is a transcriptional repressor that is involved in gene-expression regulation in very diverse biologic contexts. Information regarding the IRF2BP2 regulatory function in CD4 T lymphocytes is very limited and suggests a role for this protein in repressing the expression of different cytokine genes. Here, we showed that Irf2bp2 gene expression was decreased in CD4 T cells upon activation. To investigate the possible regulatory roles for IRF2BP2 in CD4 T cell functions, this protein was ectopically expressed in murine primary-activated CD4 T lymphocytes through retroviral transduction. Interestingly, ectopic expression of IRF2BP2 led to a reduction in CD25 expression and STAT5 phosphorylation, along with an impaired proliferative capacity. The CD69 expression was also diminished in IRF2BP2-overexpressing cells, whereas CD44 and CD62L levels were not altered. In vivo, transferred, IRF2BP2-overexpressing, transduced cells displayed an impaired expansion capacity compared with controls. Furthermore, overexpression of IRF2BP2 in differentiated Th cells resulted in slightly reduced IL-4 and pro-TGF-β production in Th2 and iT but had no effect on IFN-γ or IL-17 expression in Th1 and Th17 cells, respectively. Taken together, our data suggest a role for IRF2BP2 in regulating CD4 T cell activation by repressing proliferation and the expression of CD25 and CD69 induced by TCR stimuli.

IRF2BP2: A new player in the regulation of cell homeostasis

“…Both results demonstrated that IRF2BP2 plays an important role in lymphocyte activation. Additionally, IRF2BP2 down‐regulated CD69 expression, suggesting that IRF2BP2 participates in CD4 T‐cell activation . These studies have demonstrated that IRF2BP2 is an important regulator, which will be discussed next.…”

“…Because NFAT1 has a key role in the immune response, it is important to clarify the repressor mechanism mediated by IRF2BP2. Increasing understanding of the importance of IRF2BP2 in the immune response, the same group demonstrated that IRF2BP2 overexpression in CD4 T lymphocytes repressed the expression of IL‐2 high affinity receptor α‐chain and STAT5 phosphorylation . Both results demonstrated that IRF2BP2 plays an important role in lymphocyte activation.…”

“…In addition, IL‐2 and IL‐4 cytokine production was decreased in primary CD4 T cells by IRF2BP2 overexpression . The authors demonstrated that IRF2BP2 overexpression in primary CD4 T cells reduced cell proliferation upon activation . It also reduced the expression of the activation markers CD25 and CD69 .…”

“…In multiple myeloma, the chromosomal aberration of the most common translocation (q13;q32) found in the early stage of pathogenesis contains the IRF2BP2 gene. Having high penetrance (75%), IRF2BP2 might be a potential prognostic marker and therapeutic target in the treatment and management of multiple myeloma patients with this translocation .…”

“…Our group has contributed to understanding the role of IRF2BP2 in the immune response. The data indicate that IRF2BP2 participates in the adaptive immune response, influencing the maintenance, production, and secretion of cytokines and, consequently, resulting in T cell proliferation and activation . Initially, they demonstrated that IRF2BP2 is a partner of NFAT1, an important regulator of T cells activation and differentiation .…”