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Established cancers are frequently associated with a lymphocytic infiltrate that fails to clear the tumour mass. In contrast, the importance of recruited lymphocytes during premalignancy is less well understood. In a mouse model of premalignant skin epithelium, transgenic mice that express the human papillomavirus type 16 (HPV16) E7 oncoprotein under a keratin 14 promoter (K14E7 mice) display epidermal hyperplasia and have a predominant infiltrate of lymphocytes consisting of both CD4 and CD8 T cells. Activated, but not naïve T cells, were shown to preferentially traffic to hyperplastic skin with an increased frequency of proliferative CD8+ T cells and CD4+ T cells expressing CCR6 within the tissue. Disruption of the interaction between E7 protein and retinoblastoma tumour suppressor protein (pRb) led to reduced epithelial hyperplasia and T cell infiltrate. Finally, while K14E7 donor skin grafts are readily accepted onto syngeneic, non-transgenic recipients, these same skin grafts lacking skin-resident lymphocytes were rejected. Our data suggests that expression of a single oncoprotein in the epidermis is sufficient for lymphocyte trafficking (including immunosuppressive lymphocytes) to premalignant skin. [ABSTRACT FROM AUTHOR]

Summary Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important component of the inflammasome, functioning as an adaptor protein that facilitates the recruitment and activation of procaspases that in turn promote the maturation of interleukin-1β (IL-1β) and IL-18. Despite initial focus on the inflammatory properties of ASC there is emerging evidence that highlights the importance of ASC in facilitating adaptive immune responses. However, the cellular and molecular basis for the involvement of ASC in adaptive immunity remains largely unexplored. We have previously demonstrated that activated ASC-deficient T cells have dampened proliferative responses. We have therefore explored the underlying cellular mechanism(s) by which ASC regulates T-cell proliferation. We show that under activating conditions (anti-CD3/CD28 stimulation) in bulk T-cell cultures the presence of ASC−/− CD4+ T cells is sufficient to suppress the proliferative responses of neighbouring T cells. Furthermore, ASC−/− CD4+ T cells upon activation exhibit a suppressive cytokine profile, with elevated production of IL-10 and reduced secretion of T helper type 1 cytokines, interferon-γ and IL-2. This increase in IL-10 secretion within the activated ASC−/− CD4+ T-cell compartment was not associated with a proportional increase in conventional Foxp3+ regulatory T (Treg) cells. Interestingly, when equal numbers of fluorescence-activated cell sorted ASC+/+ and ASC−/− Treg cells (CD4+ CD44intermediate/high CD25+) were activated in vitro, the ASC−/− fraction produced significantly more IL-10 than their wild-type counterparts, suggesting that ASC−/− Treg cells have greater suppressive capacity. Collectively, these results imply that the ASC may influence the development and functioning of Treg cells. [ABSTRACT FROM AUTHOR]

The article talks about the mechanisms involved in inflammatory responses to octacalcium phosphate (OCP) crystals in a living organism. By using peritoneal model of inflammation in mice, OCP crystal–induced inflammation was detected. The article also includes the use of enzyme-linked immunosorbent assay and flow cytometry, which stated that OCP crystals induced peritoneal inflammation can be compared with those induced by monosodium urate monohydrate crystals. Crystal-induced neutrophil infiltration decreased due to the reduction of the macrophage population, concluding that macrophages are more important than the mast cells to initiate and drive OCP crystal-induced inflammation.

Deficiency of protease-activated receptor-2 (PAR2) modulates inflammation in several models of inflammatory and autoimmune disease, although the underlying mechanism(s) are not understood. PAR2 is expressed on endothelial and immune cells, and is implicated in dendritic cell (DC) differentiation. We investigated in vivo the impact of PAR2 activation on DCs and T cells in PAR2 wild-type (WT) and knockout (KO) mice using a specific PAR2 agonist peptide (AP2). PAR2 activation significantly increased the frequency of mature CD11chigh DCs in draining lymph nodes 24 hr after AP2 administration. Furthermore, these DCs exhibited increased expression of major histocompatibility complex (MHC) class II and CD86. A significant increase in activated (CD44+ CD62−) CD4+ and CD8+ T-cell frequencies was also observed in draining lymph nodes 48 hr after AP2 injection. No detectable change in DC or T-cell activation profiles was observed in the spleen. The influence of PAR2 signalling on antigen transport to draining lymph nodes was assessed in the context of delayed-type hypersensitivity. PAR2 WT mice that were sensitized by skin-painting with fluorescein isothiocyanate (FITC) to induce delayed-type hypersensitivity possessed elevated proportion of FITC+ DCs in draining lymph nodes 24 hr after FITC painting when compared with PAR2 KO mice (0·95% versus 0·47% of total lymph node cells). Collectively, these results demonstrate that PAR2 signalling promotes DC trafficking to the lymph nodes and subsequent T-cell activation, and thus provides an explanation for the pro-inflammatory effect of PAR2 in animal models of inflammation. [ABSTRACT FROM AUTHOR]

Expansion of high- or low-avidity CD8 T cells in vitro inversely correlates with the concentration of peptide ligand present during culture. In contrast, the selective enrichment of high- or low-avidity T cell populations in vivo using peptide immunisation is not well documented. In our study, a single immunisation with different doses of wild-type peptide or a variant peptide able to stimulate CTL responses cross-reactive with wild-type peptide failed to shift the average avidity of the responding CD8 T cell population specific to either peptide. However, in contrast to homologous prime-boost immunisation, heterologous prime-boost immunisation incorporating high doses of the second immunogen resulted in peptide-specific CD8 T cell populations polarized toward a low average functional avidity. These data suggest that sequential exposure to structurally related viral peptides could impair rather than promote anti-viral immunity by lowering the avidity of the responding CD8 T cell population. This study has implications for improving vaccine strategies against viruses and tumours and enhances our understanding of heterologous immunity during sequential viral infection. [ABSTRACT FROM AUTHOR]

Several corrections to articles by Mariz and colleagues, Narayan and colleagues, and the American College of Rheumatology Audiovisual Aids Committee that were published in the May 2011 issue are presented.