Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4 T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling. Moreover, RHOA G17V expression together with Tet2 loss resulted in development of AITL in mice. Importantly, Tet2RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation.

Early studies described CD69 as a leukocyte activation marker, and suggested its involvement in the activation of different leukocyte subsets as well as in the pathogenesis of chronic inflammation. However, recent investigations have showed that CD69 knockout mice exhibit an enhanced susceptibility to different inflammatory diseases, mainly those mediated by Th17 lymphocytes. The recent discovery of a ligand for CD69 expressed on Dendritic cells, Galectin-1, has confirmed the immunoregulatory role of CD69 mainly by the inhibition of Th17 differentiation and function in mice and humans. In this regard, the expression of CD69, both in Th17 lymphocytes and by a subset of regulatory T cells, has an important role in the control of the immune response and the inflammatory phenomenon. Therefore, different evidences indicate that CD69 exerts a complex immuno-regulatory role in humans, and that it could be considered as target molecule for the therapy of immune-mediated diseases. Keywords CD69; Inflammatory diseases; Treg lymphocytes; Th17 lymphocytes, Immuno-regulation CD69 IS AN EARLY ACTIVATION ANTIGEN OF IMMUNE CELLSCD69 is a type II C-lectin membrane receptor with a scarce expression in resting lymphocytes that is rapidly induced upon cell activation. CD69 gene maps at human chromosome 12, and behaves as an early activation gene that contains responsive elements for the transcription factors NF-κB, ERG-1 and AP-1 (Fig. 1A). Early in vitro data as well as the prominent expression of CD69 in chronic inflammatory cell infiltrates suggested that this receptor has an important role in the activation of leukocytes, exerting a proinflammatory effect. Recent studies in CD69-deficient mice indicate that this molecule Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts exerts a complex and interesting role in the modulation of the immune response and the inflammatory phenomenon [1]. However, these studies have been controversial for a while since two different models of CD69 deficient mice have been described with opposite effects in the development of T-cell independent arthritis and Th2-dependent asthma. Murata et al. 2003 [2] described a CD69 knockout mice that were protected towards arthritis induced by anti-type II collagen antibodies whereas Lamana et al. 2006 [3] revisited the same disease model with an independent CD69-deficient mice and found that the lack of CD69 did not inhibits joint inflammation. Lamana et al. used monoclonal antibodies against CD69 in wild type mice, that downregulates the expression of the molecule in the membrane, to bypass putative different genetic alterations in the process of generation of these two different animal models. These investigations confirmed that the lack of CD69 do not protects the mice towards the T-independent model of neutrophil-mediated arthritis.Regarding the role of CD69 in asthma, Miki-Hosokawa et al. 2009 described that the reduced migration of Th2 cells accounts for the inhibition of lung inflammation in a model of CD69 null mice [4]...

Esta es la versión de autor del artículo publicado en: This is an author produced version of a paper published in:Journal of Autoimmunity 55 (2014)

Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-α. TNF-α is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-α expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38γ/δ MAPK proteins is required for the elongation of nascent TNF-α protein in macrophages. The MKK3/6-p38γ/δ pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-α elongation. These results identify a new signaling pathway that regulates TNF-α production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-α production is involved.