All-transRetinoic Acid Stimulates IL-2-Mediated Proliferation of Human T Lymphocytes: Early Induction of Cyclin D3

Abstract

Vitamin A is established as an important immune regulator, but the mechanisms whereby vitamin A regulates T cell biology are poorly defined. In this study, we show that an active metabolite of vitamin A, all-trans retinoic acid (RA), potently stimulates T cell proliferation by modulating IL-2-mediated signaling downstream of IL-2R and independent of the induction of IL-2. Thus, at concentrations as low as 0.1 nM, RA enhanced the division of normal human T lymphocytes that were simultaneously stimulated with anti-CD3 mAbs and saturating concentrations of IL-2. At the optimal concentration of RA (50 nM), a 3-fold increase in T cell proliferation was observed. The induced proliferation was preceded by increased phosphorylation of the retinoblastoma protein and enhanced G1- to S-phase progression. Interestingly, the promitogenic effect of RA was found to be particularly directed toward increased expression of cyclin D3 at both the mRNA and protein level. Furthermore, the stimulatory effect of RA on cyclin D3 expression as well as on cell proliferation was completely abolished in the presence of the JAK inhibitor AG-490 or blocking IL-2Rα mAbs, and RA also enhanced cyclin D3 expression and T cell proliferation in the presence of IL-2 alone. Finally, we showed that the proliferative effect of RA was mimicked by agonists of the retinoic acid receptor (RAR) and completely inhibited by a RAR-selective antagonist. In conclusion, our results indicate that RA, via RAR, stimulates IL-2-induced signaling in a JAK-dependent manner to enhance cyclin D3 expression and thereby promote T cell proliferation.

Aberrant expression of aldehyde dehydrogenase 1A (ALDH1A) subfamily genes in acute lymphoblastic leukaemia is a common feature of T‐lineage tumours

“…Conversely, treatment with a pan-RAR agonist specifically stimulated proliferation of the T-ALL cell lines while no such stimulation occurred in the B-lineage lines within the concentration range used. These data are consistent with previous studies in humans and mice which have shown that RA is stimulatory to T lymphocyte growth (Dillehay et al, 1989;Jiang et al, 1993;Ertesvag et al, 2002;Seguin-Devaux et al, 2005;Engedal et al, 2006) but inhibitory to the growth of B lymphocytes (Bosma & Sidell, 1988;Fahlman et al, 1995;Naderi & Blomhoff, 1999), while promoting B cell differentiation (Chen et al, 2008). This provides a plausible explanation for why aberrant ALDH1A expression is almost completely restricted to ALL tumours of T cell phenotype.…”

“…Consistent with this, RA has been documented to enhance normal human T cell proliferation (Dillehay et al, 1989;Ertesvag et al, 2002;Engedal et al, 2006). To extend these findings to the tumour setting, we assessed the functional importance of RA synthesizing ALDH1A enzymes, together with RA signalling via RARA, to the proliferation of T-ALL cell lines (PER-117, PER-255, PER-604, CEM), which were compared with those of B lineage .…”

“…Moreover, in haemopoietic progenitors ALDH1A expression appears to have a role in regulating the polarity of differentiation towards a myeloid rather than a lymphoid cell fate (Storms et al, 2005;Rice et al, 2008), an effect mirrored by the administration of RA alone (Purton et al, 1999;Leung & Verfaillie, 2005). Significantly, RA is known to promote the proliferation (Dillehay et al, 1989;Ertesvag et al, 2002;Engedal et al, 2006) and survival (Engedal et al, 2004) of human T cells, while inhibiting thymocyte differentiation (Zhou et al, 2008). This is in contrast to many other cell types, including B cells (Naderi & Blomhoff, 1999), where RA primarily appears to act as an anti-proliferative and prodifferentiation agent.…”

Human basophils activated by mast cell–derived IL-3 express retinaldehyde dehydrogenase-II and produce the immunoregulatory mediator retinoic acid

“…13,36 To unravel a possible immunoregulatory role of endogenous basophilderived RA, purified basophils were coincubated with autologous naive T cells activated by anti-CD3/CD28 antibodies in the presence or absence of IL-3 and/or RAR antagonist. IL-3 itself did not affect T cells ( Figure S3), but in the presence of basophils we observed a remarkable IL-3-induced up-regulation of the ␣4/␤7 integrin, a ligand for Mad-CAM and VCAM ( Figure 6A).…”

Retinoic Acid as a Vaccine Adjuvant Enhances CD8+T Cell Response and Mucosal Protection from Viral Challenge

“…Dendritic cells (DCs) from gut-associated tissues, including mesenteric lymph nodes (LN) (MLN), lamina propria (LP), and Peyer's patches (PP), express the enzymes necessary to convert vitamin A into ATRA (25,27,59). ATRA can enhance T cell proliferation (12) and upregulate the expression of gut-homing receptors on T cells in vitro (25,28,40,57). CD4 ϩ and CD8 ϩ T cells primed in vitro in the presence of ATRA or DCs isolated from intestinal sites express high levels of the integrin ␣4␤7 and the chemokine receptor CCR9, which, upon binding to MAdCAM-1 and CCL25, respectively, mediate the migration of T cells to gut mucosa (25,28,53).…”