Psoriasis is a common T-cell-mediated skin disease with 2-3% prevalence worldwide. Psoriasis is considered to be an autoimmune disease, but the precise nature of the autoantigens triggering T-cell activation remains poorly understood. Here we find that two-thirds of patients with moderate-to-severe plaque psoriasis harbour CD4 þ and/or CD8 þ T cells specific for LL37, an antimicrobial peptide (AMP) overexpressed in psoriatic skin and reported to trigger activation of innate immune cells. LL37-specific T cells produce IFN-g, and CD4 þ T cells also produce Th17 cytokines. LL37-specific T cells can infiltrate lesional skin and may be tracked in patients blood by tetramers staining. Presence of circulating LL37-specific T cells correlates significantly with disease activity, suggesting a contribution to disease pathogenesis. Thus, we uncover a role of LL37 as a T-cell autoantigen in psoriasis and provide evidence for a role of AMPs in both innate and adaptive immune cell activation.

CD28 is one of the most important costimulatory receptors necessary for full T lymphocyte activation. The CD28 receptor can enhance T cell antigen receptor (TCR) signals, as well as deliver independent signals. Indeed, CD28 engagement by B7 can generate TCR-independent signals leading to I B kinase and NF-B activation. Here we demonstrate that the TCR-independent CD28 signal leads to the selective transcription of survival (Bcl-xL) and inflammatory (IL-8 and B cell activation factor, but not proliferative (IL-2), genes, in a NF-Bdependent manner. CD28-stimulated T cells actively secrete IL-8, and Bcl-xL up-regulation protects T cells from radiation-induced apoptosis. The transcription of CD28-induced genes is mediated by the specific recruitment of RelA and p52 NF-B subunits to target promoters. In contrast, p50 and c-Rel, which preferentially bind NF-B sites on the IL-2 gene promoter after anti-CD3 stimulation, are not involved. Thus, we identify CD28 as a key regulator of genes important for both survival and inflammation. C D28 is one of the most important costimulatory receptors necessary for full T lymphocyte activation. Early studies on CD28 demonstrated that it provides a potent signal for the upregulation of several cytokines, acting at the level of both transcription and message stability. More recent studies have evidenced that CD28 plays a key role in enhancing T cell activation by the T cell antigen receptor (TCR) (1). As an integral component of the immunological synapse, CD28 plays a critical role in the recruitment of signaling molecules to the TCR (2). In particular, it has been recently demonstrated that CD28 enhances close contact between T cells and antigen-presenting cells and facilitates TCR signal transduction by amplifying phospholipase C␥1 activation and Ca 2ϩ response (3). The consequence of this action is an augmentation of early TCR-mediated signal (4). Recent evidence showing that CD28 can mediate adhesion signals beyond costimulatory ones (3) has led to new interest and induced a new wave of investigation of the intriguing problems concerning the molecular mechanisms as well as the targets of CD28 as an independent signaling unit. CD28 stimulation can induce cytoskeletal rearrangements in T cells (5) or up-regulate IL-2-4 only when Vav and the adapter SLP-76 are overexpressed (6). However, the mediators and the molecular mechanisms, which govern the process whereby CD28 may deliver an autonomous signal, remain unknown. We have recently demonstrated that CD28 engagement by B7 can generate TCRindependent signals leading to I B kinase (IKK) and NF-B activation (7) and that Vav-1 acts as the upstream regulator of this signaling pathway (8).NF-B͞Rel transcription factors are critical regulators of the positioning of immune responses to integrate information from both innate and adaptive immune signaling pathways. In mammals, this family consists of five members that form homo-and heterodimeric complexes including NF-B1 (p50 and its precursor p105), NF-B2 (p52 and its precursor p100), RelA...

Background/Aims: Hepatitis C virus (HCV) infection results in a high frequency of chronic disease. The aim of this study was to identify early prognostic markers of disease resolution by performing a comprehensive analysis of viral and host factors during the natural course of acute HCV infection. Methods: The clinical course of acute hepatitis C was determined in 34 consecutive patients. Epidemiological and virological parameters, as well as cell mediated immunity (CMI) and distribution of human leukocyte antigens (HLA) alleles were analysed. Results: Ten out of 34 patients experienced self-limiting infection, with most resolving patients showing fast kinetics of viral clearance: at least one negative HCV RNA test during this phase predicted a favourable outcome. Among other clinical epidemiological parameters measured, the self-limiting course was significantly associated with higher median peak bilirubin levels at the onset of disease, and with the female sex, but only the latter parameter was independently associated after multivariate analysis. No significant differences between self-limiting or chronic course were observed for the distribution of DRB1 and DQB1 alleles. HCV specific T cell response was more frequently detected during acute HCV infection, than in patients with chronic HCV disease. A significantly broader T cell response was found in patients with self-limiting infection than in those with chronic evolving acute hepatitis C. Conclusion:The results suggest that host related factors, in particular sex and CMI, play a crucial role in the spontaneous clearance of this virus. Most importantly, a negative HCV RNA test and broad CMI within the first month after onset of the symptoms represent very efficacious predictors of viral clearance and could thus be used as criteria in selecting candidates for early antiviral treatment.

CD28‐delivered costimulatory signals are required to induce NF‐κB activation in response to TCR stimulation. We have recently demonstrated that the mitogen‐activated kinase kinase 1 (MEKK1), a kinase known to regulate the c‐jun N‐terminal kinase (JNK) pathway, is also involved in the CD28‐ and TCR‐induced inhibitor of κB factor (IκB) kinases (IKK) and NF‐κB activation. Searching for molecules that couple TCR and CD28 to MEKK1, we found that the guanine nucleotide exchange factor Vav synergized with CD28 stimulation in Jurkat cells to induce NF‐κB transcriptional activity through the activation of IKKα and IKKβ. Dominant negative mutants of Vav inhibited TCR‐ and CD28‐NF‐κB‐dependent transcription by interfering with the activation of the IKK complex. Blocking Rac signaling downstream of Vav by dominant negative RacN17 exerts similar effects on IKK and NF‐κB activation after TCR/CD28 stimulation. Finally, Vav‐induced NF‐κB activation in CD28 costimulated cells was inhibited by dominant negative MEKK(KM). These results identify Vav, Rac‐1 and MEKK1 as components of a common pathway regulating both NF‐κB and AP‐1 that contributes to full activation of the CD28 response element (CD28RE).

Our data provide evidence of strong and multispecific T cell responses with a sustained ability to proliferate in response to antigen stimulation as reliable pharmacodynamic measures of a protective CMI during acute infection, and suggest that early impairment of proliferation may contribute to loss of T cell response and chronic HCV persistence.