CD69 is a membrane-bound, type II C-lectin receptor. It is a classical early marker of lymphocyte activation due to its rapid appearance on the surface of the plasma membrane after stimulation. CD69 is expressed by several subsets of tissue resident immune cells, including resident memory T (TRM) cells and gamma delta (γδ) T cells, and is therefore considered a marker of tissue retention. Recent evidence has revealed that CD69 regulates some specific functions of selected T-cell subsets, determining the migrationretention ratio as well as the acquisition of effector or regulatory phenotypes. Specifically, CD69 regulates the differentiation of regulatory T (Treg) cells as well as the secretion of IFN-γ, IL-17, and IL-22. The identification of putative CD69 ligands, such as Galectin-1 (Gal-1), suggests that CD69-induced signaling can be regulated not only during cognate contacts between T cells and antigen-presenting cells in lymphoid organs, but also in the periphery, where cytokines and other metabolites control the final outcome of the immune response. Here, we will discuss new aspects of the molecular signaling mediated by CD69 and its involvement in the metabolic reprogramming regulating TH-effector lineages.Keywords: CD69 r Galectin-1 r LAT1 r Metabolism r mTOR r S1P1 r T cells IntroductionCD69 is a disulfide-linked homodimer protein with two differentially glycosylated subunits (28-32 kDa). Each subunit consists of an extracellular C-type lectin domain (CTLD) connected with a single-spanning transmembrane region followed by a short cytoplasmic tail (Fig. 1). The CD69 gene is located in the natural killer (NK) gene cluster, chromosome 6 in mouse and 12 in human [1,2]. Binding sites for several inducible transcriptional factors such as nuclear factor (NF)-κB, erythroblast transformationspecific related gene-1 (ERG-1) and activator protein-(AP-) 1 are located within the CD69 gene promoter [3,4]. CD69 expression is readily upregulated upon activation in most leukocytes, which underlies its widespread use as a marker of activated lymphocytes and NK cells, mainly [5]. In addition to its intrinsic value as an Correspondence: Dr. Francisco Sánchez-Madrid e-mail: fsmadrid@salud.madrid.org activation marker, recent evidence suggests that CD69 is also an important regulator of immune responses. Although the precise role of CD69 expression on immune cells function is yet to be elucidated, accumulating experimental evidence has revealed that CD69 may determine patterns of cytokine release as well as homing and migration of activated lymphocytes. In this review, we aim to update the state of the art regarding the functional role of CD69 in the regulation of the immune responses. We offer an integrated perspective of the mechanisms that drive the immune effects mediated by CD69 as well as potential synergies and antagonisms with other signaling routes involved in the immune response. CD69 is an early activation markerCD69 expression is rapidly induced on the surface of T lymphocytes after TCR/CD3 engagement, activating cy...

Increased formation of MG (methylglyoxal) and related protein glycation in diabetes has been linked to the development of diabetic vascular complications. Diabetes is also associated with impaired wound healing. In the present study, we investigated if prolonged exposure of rats to MG (50-75 mg/kg of body weight) induced impairment of wound healing and diabetes-like vascular damage. MG treatment arrested growth, increased serum creatinine, induced hypercholesterolaemia (all P < 0.05) and impaired vasodilation (P < 0.01) compared with saline controls. Degenerative changes in cutaneous microvessels with loss of endothelial cells, basement membrane thickening and luminal occlusion were also detected. Acute granulation appeared immature (P< 0.01) and was associated with an impaired infiltration of regenerative cells with reduced proliferative rates (P < 0.01). Immunohistochemical staining indicated the presence of AGEs (advanced glycation end-products) in vascular structures, cutaneous tissue and peripheral nerve fibres. Expression of RAGE (receptor for AGEs) appeared to be increased in the cutaneous vasculature. There were also pro-inflammatory and profibrotic responses, including increased IL-1beta (interleukin-1beta) expression in intact epidermis, TNF-alpha (tumour necrosis factor-alpha) in regions of angiogenesis, CTGF (connective tissue growth factor) in medial layers of arteries, and TGF-beta (transforming growth factor-beta) in glomerular tufts, tubular epithelial cells and interstitial endothelial cells. We conclude that exposure to increased MG in vivo is associated with the onset of microvascular damage and other diabetes-like complications within a normoglycaemic context.

In many cell types, nuclear A-type lamins have been implicated in structural and functional activities, including higher-order genome organization, DNA replication and repair, gene transcription, and signal transduction. However, their role in specialized immune cells remains largely unexplored. Here, we showed that the abundance of A-type lamins is almost negligible in resting naïve T lymphocytes, but that it is substantially increased upon activation of the T cell receptor (TCR), and is an early event that accelerates formation of the immunological synapse between T cells and antigen-presenting cells. We found that lamin-A enhanced the polymerization of F-actin in T cells, a critical step for immunological synapse formation, by physically connecting the nucleus to the plasma membrane through the linker of nucleoskeleton and cytoskeleton (LINC) complex. We also showed that lamin-A played a key role in other membrane, cytoplasmic, and nuclear events related to TCR activation, including receptor-clustering, downstream signaling, and target gene expression. Notably, the presence of lamin-A was associated with enhanced extracellular signal-regulated kinase 1/2 signaling, and pharmacological inhibition of this pathway reduced the extent of lamin-A-dependent T cell activation. Moreover, mice deficient in lamin-A exhibited impaired T cell responses in vivo. These findings underscore the importance of A-type lamins for TCR activation, and identify lamin-A as a previously unappreciated regulator of the immune response.

In the version of the article originally published, in the top immunoblot (loading control) in Figure 5f, the right half was incorrectly a mirror-image duplication of the left half. The correct immunoblot from a replicate experiment is now presented (along with the corresponding bottom immunoblot). In the version of this article initially published online, the identification of dermal and epidermal γδ T cells in the legend for Figure 3f was reversed; a label was missing above the far left column of Figure 4c; and the red and blue lines were switched in the keys for the far right plots in Figure 6i. The legend for Figure 3f should read "...identified by high expression (top right; epidermal) or low expression (bottom right; dermal) of the γδ TCR. " The far left column in Figure 4c should include the label "CD69-KO" above. The correct keys for Figure 6i are as follows: blue line, FIZC (37 °C), and red line, FICZ + BCH (37 °C); and blue line, CD69-KO (37 °C), and red line, WT (37 °C).

A novel inhibitor of interactions between signaling proteins in T cells demonstrates promising preventive and therapeutic effects in several models of autoimmune disease.

Keratinocytes and skin immune cells are actively metabolizing nutrients present in their microenvironment. This is particularly important in common chronic inflammatory skin diseases such as psoriasis and atopic dermatitis, characterized by hyperproliferation of keratinocytes and expansion of inflammatory cells, thus suggesting increased cell nutritional requirements. Proliferating inflammatory cells and keratinocytes express high levels of glucose transporter (GLUT)1, L-type amino acid transporter (LAT)1, and cationic amino acid transporters (CATs). Main metabolic regulators such as hypoxia-inducible factor (HIF)-1α, MYC, and mechanistic target of rapamycin (mTOR) control immune cell activation, proliferation, and cytokine release. Here, we provide an updated perspective regarding the potential role of nutrient transporters and metabolic pathways that could be common to immune cells and keratinocytes, to control psoriasis and atopic dermatitis.

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Recent evidence on HDAC6 function underlines its role as a key protein in the innate immune response to viral infection. However, whether HDAC6 regulates innate immunity during bacterial infection remains unexplored. To assess the role of HDAC6 in the regulation of defence mechanisms against intracellular bacteria, we used the Listeria monocytogenes (Lm) infection model. Our data show that Hdac6-/- bone marrow-derived dendritic cells (BMDCs) have a higher bacterial load than Hdac6+/+ cells, correlating with weaker induction of IFN-related genes, pro-inflammatory cytokines and nitrite production after bacterial infection. Hdac6-/- BMDCs have a weakened phosphorylation of MAPK signalling in response to Lm infection, suggesting altered Toll-like receptor signalling (TLR). Compared with Hdac6+/+ counterparts, Hdac6-/- GM-CSF-derived and FLT3L-derived dendritic cells show weaker pro-inflammatory cytokine secretion in response to various TLR agonists. Moreover, HDAC6 associates with the TLR-adaptor molecule Myeloid differentiation primary response gene 88 (MyD88), and the absence of HDAC6 seems to diminish the NF-κB induction after TLR stimuli. Hdac6-/- mice display low serum levels of inflammatory cytokine IL-6 and correspondingly an increased survival to a systemic infection with Lm. The impaired bacterial clearance in the absence of HDAC6 appears to be caused by a defect in autophagy. Hence, Hdac6-/- BMDCs accumulate higher levels of the autophagy marker p62 and show defective phagosome-lysosome fusion. These data underline the important function of HDAC6 in dendritic cells not only in bacterial autophagy, but also in the proper activation of TLR signalling. These results thus demonstrate an important regulatory role for HDAC6 in the innate immune response to intracellular bacterial infection.