A common immunopathological hallmark of many autoimmune inflammatory diseases is a T-cell invasion and accumulation at the inflamed tissue. Although the exact molecular and microenvironmental mechanisms governing such cellular invasion and tissue retention are not known, some key immunological principles must be at work. Transforming growth factor-b (TGF-b) is known to modulate some of these processes including homing, cellular adhesion, chemotaxis and finally T-cell activation, differentiation and apoptosis. The chronicity of such T-cell-driven inflammation probably involves an innate immunological response leading to a T-1 (Th/Tc), T-2 or T-3 (Th/Tr) T-cell adaptive immune response. Several studies suggest that the key to T-cell final destination resides on its and the antigen-presenting cell's phenotype as well as the coreceptor expression pattern and their signalling intensity. Recent observations suggest other equally important regulatory elements of T-cell inflammatory response that are sensitive to TGF-b modulation. These include: (i) the stage of T-cell activation/differentiation; (ii) the chemotactic/adhesion molecule expression pattern; and (iii) the conditioning at the immunological synapse determining their sensitivity to known regulators such as TGF-b. In this article, we focus on how the phenotype of the responding T cell and the T-cell receptor (TCR)-signalling intensity could drive the given inflammatory response. In particular, we discuss how TGF-b can influence the process of T-cell migration and activation during such site-specific inflammation.

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The pathogenicity of extracellular products (ECPs) from 24 atypical Aeromonas salmonicida strains was studied with respect to  : lethality in Atlantic salmon, pathogenic effect in muscle, haemolytic activity, cytotoxicity in two fish cell lines and proteolytic activities. Furthermore, the relationship between lethality of ECPs and mortality caused by bacterial challenge was examined. Correlation was demonstrated between the pathogenic properties and proteolytic activities of the ECPs. Cytolytic (GCAT) activity comparable with that of the typical reference strain used (NCMB 1102) was not detected in ECPs of any of the atypical strain tested. An extracellular metallo‐caseinase, AsaP1, was linked with lethal toxicity and a strong pathogenic effect. Furuncular‐like lesions were produced by ECPs containing AsaP1 activity. One strain produced a lethal toxin which was neither caseinolytic nor with GCAT comparable activity. The examined atypical strains form at least three distinct groups based on different virulence mechanisms and extracellular proteases.

Objective. To evaluate the production of interleukin-10 (IL-10) as well as levels of IgG and antinuclear antibodies (ANA) in systemic lupus ery-thematosus (SLE) patients and their first-degree relatives and spouses in Icelandic SLE multicase families. Methods. IL-10 production was studied by enzyme-linked immunospot assay of freshly isolated peripheral blood mononuclear cells. Total IgG and ANA were also investigated. Subjects consisted of 23 SLE patients and 47 of their first-degree relatives in 9 Icelandic multicase families. Subjects were ethnically matched by a group of healthy controls. A separate study investigated 12 SLE patients (also from SLE multicase families) and their spouses and a matched group of healthy controls. A predefined protocol was used to obtain both clinical and laboratory data, including information about SLE and other autoimmune disorders. Results. The SLE patients had a significantly higher number of IL-10-producing cells compared with both first-degree relatives and healthy controls (P 0.0005 and P < < < 0.0001, respectively). First-degree relatives also had a significantly higher number of IL-10-producing cells compared with healthy controls (P 0.01). This was also true for the spouses of SLE patients, who had a higher number of IL-10-producing cells compared with matched healthy controls (P 0.02). Conclusion. SLE patients and their first-degree relatives, as well as a limited number of healthy spouses of SLE patients, had increased numbers of spontaneous IL-10-producing cells. These data support the hypothesis that IL-10 production may be genetically determined , and may predispose one toward development of SLE. This has previously been suggested by studies of SLE patients and their relatives in another ethnic population, using another method for measuring IL-10 production. Although these data are based on a small number of observations, they suggest that not only genetic but also environmental factors may be of importance in determining IL-10 production, since the spouses of SLE patients also had an increased number of IL-10-producing cells.

TGF-beta1 is a powerful regulator of various T-cell functions. However, it has been unclear how the T-cell responsiveness towards TGF-beta1 is affected by its phenotype or signaling intensity. In the present study, we demonstrate that the phenotype and the TCR-signaling intensity of the responding T-cell as well as the presence of anti-CD28 co-stimulation markedly affects how naïve human cord blood T-cells respond to TGF-beta1. In this report we demonstrate that the strength of the stimulatory signal modifies the T-cell response towards TGF-beta1. Thus, the greatest anti-proliferative effect of TGF-beta1 was observed during weak stimulatory conditions (low dose of anti-CD3 with no co-stimulatory signal). However, such anti-proliferative effect was reduced during strong stimulatory signal (high dose of anti-CD3 with a CD28-directed co-stimulatory signal). In addition, our results indicate that CD8+ T-cells are generally more responsive towards TGF-beta1 than CD4+ T-cells. To our surprise, naïve T-cells had a skewed Th1/Tc1 cytokine secretion pattern with high amounts of IL-2, IFNgamma and TNFalpha, but low amounts of IL-4, IL-5 and IL-10. TGFbeta1 significantly reduced the secretion of IL-2 and IFNgamma, but such suppression was partially prevented by anti-CD28-induced co-stimulation. In contrast, the inhibitory effect on IL-5 secretion was unaffected by anti-CD28 co-stimulation. Interestingly, TGF-beta1 induced IL-10 and TNFalpha secretion. However, the induction of IL-10 secretion was reduced during optimal stimulatory conditions while TGF-beta1 further induced TNFalpha secretion. These data demonstrate that the duration, intensity and type of signaling alters the sensitivity of T-cells to powerful immunological modifying agents like TGF-beta1.

The abundances of Aeromonas satmonicida subsp. salmonicida in the water and in the surface microlayer was studied during the initial phase of a cohabitant infection experiment with Atlantic salmon, Salmo salar L.. smolt. Aeromonas salmonicida was detected in the water samples only until the intraperitoneally infected smolt were dead and had been removed. In the lipid rich surface microlayer. A. salmonicida was detected in high concentrations from the day of the first fish mortality and throughout the rest of the experiment. The significance of the high cell surface hydrophobicity is discussed as a possible reason for enrichment of A. salmonicida at the air-water interface.

The expression of the integrin aE (CD103), may enhance the retention of regulatory T cells to peripheral inflammatory sites and possibly contribute to their suppressive potential. The aim of this study was to define the regulatory role of IL-2 and TGF-b1 on the CD103 expression and the optimal in vitro conditions for the induction/expansion of human CD4 + and CD8 + Tregs. Cord blood mononuclear cells (CBMC) were stimulated under various culture conditions, including anti-CD3, anti-CD28, IL-2 and TGF-b1. TGF-b1 and IL-2 were both required for optimal expression of CD103. In addition, TGF-b1 and IL-2 synergistically induced CD103 expression on CD8 + T cells, whereas, only additive induced expression was noted on CD4 + T cells. Surprisingly, CD103 expression was not dependent upon CD28 costimulation. IL-2 also played a central role in CD103 expression by CD25 hi Foxp3+ Tregs. IL-2, TGFb1 and anti-CD3 defined the optimal stimulatory conditions favouring the induction/expansion of both CD4 + and CD8 + human Tregs from naive CBMC. Thus, this study provides new insights into the regulatory role of IL-2 upon CD103 expression by human cord blood CD4 + and CD8 + T cells. Furthermore, it identifies the in vitro culture conditions driving the differentiation of the novel phenotype CD4 + and CD8 + CD103 + CD25 hi Foxp3+ Tregs from human CBMC.

Tumour necrosis factor alpha (TNFalpha) inhibitors are widely used successfully as immunomodulatory agents in various autoimmune diseases. They primarily target the direct pro-inflammatory effect of TNFalpha. They have also been found to be critical for T-cell viability and activation. In this study we evaluated the effect of infliximab treatment under different in vitro stimulatory conditions of naive human cord blood T-cells and adult peripheral blood mononuclear cells (PBMC). PBMC and negatively selected cord blood naive human T-cells were stimulated with alphaCD3 with or without alphaCD28 co-stimulation. The role of in vitro infliximab treatment was evaluated in relation to transforming growth factor-beta1 (TGF-beta1) under the above different stimulatory conditions. Anti-TNFalpha treatment with infliximab significantly suppressed proliferation of adult and cord blood T-cells (P < 0.013) during suboptimal stimulatory conditions. Infliximab prevented division of naive CD4+ and CD8+ T-cells and consequently also activation induced cell death, which was induced after three cell divisions. Interleukin (IL)-2 secretion was significantly decreased during infliximab treatment of suboptimally stimulated T-cells (P < 0.05) while TGF-beta1 levels were unchanged. Strikingly, the anti-proliferative effect of infliximab was overcome by the administration of anti-TGF-beta1 or by the addition of exogenous IL-2. Interestingly, CD28 mediated co-stimulation restored the proliferative response in a dose-responsive manner during infliximab treatment. Finally, exogenous TNFalpha administration during suboptimal stimulation reduced the inhibitory effect of TGF-beta1 upon proliferation (P < 0.03). These results demonstrate that anti-TNFalpha treatment is primarily working upon T cells under low stimulatory conditions and probably through TGF-beta1.