CD4⁺CD25⁺ regulatory T lymphocytes (Tregs) are specialized T cells playing a key role in the control of immune homeostasis. Here, we show that human Tregs constitutively express tyrosine hydroxylase (TH, EC 1.14.16.2), the rate-limiting enzyme in the synthesis of catecholamines, and contain substantial amounts of dopamine, norepinephrine, and epinephrine, which are released upon treatment with reserpine. Catecholamine release results in reduced production of interleukin-10 and transforming growth factor-β by Tregs, and in down-regulation of Treg-dependent inhibition of effector T-lymphocyte (Teff) proliferation, which occurs without affecting the production of tumor necrosis factor-α or interferon-γ. Tregs and Teffs express on the cell membrane both D1-like and D2-like dopaminergic receptors to a similar extent (12%-29% of the cells). Catecholamine-dependent down-regulation of Tregs is, however, selectively reversed by pharmacological blockade of dopaminergic D1-like receptors, which in Tregs only (and not in Teffs) are also expressed at the level of mRNA and are functionally coupled to intracellular production of cAMP. These findings indicate that in human Tregs endogenous catecholamines subserve an autocrine/paracrine loop involving dopaminergic pathways and resulting in down-regulation of Treg function.

The potential for interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) to induce neutrophil and mononuclear phagocyte accumulation in the lungs of patients with pulmonary sarcoidosis and idiopathic pulmonary fibrosis (IPF) was investigated. Bronchoalveolar lavage (BAL) fluids from 12 patients with IPF and 15 with sarcoidosis were concentrated by reversed-phase chromatography, and their IL-8 and MCP-1 concentrations assessed by enzyme-linked immunosorbent assay (ELISA), chemotaxis, and enzyme-releasing assays with monocytes and neutrophils. ELISA revealed significantly elevated concentrations of MCP-1 (20.1 ng/mg albumin) in the BAL fluids of patients with pulmonary sarcoidosis and those with IPF (41.8 ng/mg) in comparison to 11 normal individuals (4.24 ng/mg) and 15 patients with chronic bronchitis (CB) (5.16 ng/mg). Similarly, the chemotactic activity for monocytes (MCP-1 equivalent) was strongly increased in patients with sarcoidosis (86.03 ng/mg) as well as in those with IPF (54.47 ng/mg). The chemoattractant activity of normal individuals and CB patients was 7- or 3-fold lower, respectively. Patients with IPF and sarcoidosis also had elevated IL-8 levels (15.5 and 26.0 ng/mg, respectively; normals: 2.14 ng/mg; and CB patients: 4.23 ng/mg) and greater neutrophil chemotaxis (60.25 and 49.68 ng/mg, respectively; normals: 0.35 ng/mg; and CB patients: 11.06 ng/mg). These data suggest that increased levels of both MCP-1 and IL-8 may be characteristic for sarcoidosis or IPF. It appears likely that both of these chemoattractants contribute to the influx of monocytes and neutrophils into the pulmonary alveolus and interstitium in these diseases.

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group’s cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The “ex-novo” occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies’ positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.

Absolute and human cytomegalovirus (HCMV)-specific CD4⁺ and CD8⁺ T-cell counts were monitored in 38 solid organ (20 heart, 9 lung and 9 kidney) transplant recipients during the first year after transplantation by a novel assay based on T-cell stimulation with HCMV-infected autologous dendritic cells. According to the pattern of T-cell restoration occurring either within the first month after transplantation or later, patients were classified as either early (n = 21) or late responders (n = 17). HCMV-specific CD4⁺ and CD8⁺ T-cell counts were consistently lower in late compared to early responders from baseline through 6 months after transplantation. In addition, in late responders, while HCMV infection preceded immune restoration, HCMV-specific CD4⁺ restoration was significantly delayed with respect to CD8⁺ T-cell restoration. The number of HCMV-specific CD4⁺ and CD8⁺ T-cells detected prior to transplantation significantly correlated with time to T-cell immunity restoration, in that higher HCMV-specific T-cell counts predicted earlier immune restoration. Clinically, the great majority of early responders (18/21, 85.7%) underwent self-resolving HCMV infections (p = 0.004), whereas the great majority of late responders (13/17, 76.5%) were affected by HCMV infections requiring antiviral treatment (p = <0.0001). Simultaneous monitoring of HCMV infection and HCMV-specific T-cell immunity predicts T-cell-mediated control of HCMV infection.