709M yocardial infarction and stroke caused by atherosclerosis are the most frequent cardiovascular causes of death and disability in the world despite the progress in prevention and therapy.1 Recent evidence clearly implicates the innate and adaptive immune system in the pathogenesis of atherosclerosis.2 T lymphocytes, the main orchestrators of adaptive immune responses, have pivotal roles in atherosclerosis. In particular, proinflammatory CD4+ T lymphocytes such as T helper 1 cells have been shown to promote atherosclerosis in animal models and constitute the predominant T cells in human atherosclerotic plaques. [3][4][5] We and others have demonstrated that CD4 + CD28null T cells, a unique subset of T helper 1 lymphocytes characterized by the lack of costimulatory receptor CD28, are present in high numbers in the circulation and atherosclerotic plaques of patients with acute coronary syndrome (ACS), 6-8 but these cells are not present in healthy individuals. Moreover, CD4 + CD28null T cells (from now on abbreviated as CD28 null T cells) produce higher levels of inflammatory cytokines interferon-γ and tumor necrosis factor-α than conventional CD4 + CD28+ (CD28 + ) T cells. 6,9 In stark contrast to CD28 + T lymphocytes, CD28 null T cells release cytotoxic molecules (ie, perforin and granzymes) 6 that are instrumental in killing endothelial and vascular smooth muscle cells in vitro. 10 These properties suggest that CD28 null T cells have harmful effects in atherosclerosis, although a direct causal link is yet to be established, because this subset of T cells is present only in humans with an equivalent population absent in mice. Recently, we were the first to show that the distinguishing feature between CD28 null and conventional CD28 + T cells in ACS patients is a significantly higher expression on CD28 null T cells of alternative costimulatory receptors . We further demonstrated that 4-1BB and OX40 have critical roles in regulating the production of inflammatory cytokines interferon-γ and tumor necrosis factor-α and perforin release from CD28 null T cells in ACS. 6 In addition to their roles in T-cell costimulation, 4-1BB and OX40 are important for the survival of T cells. 11,12 As mentioned, ACS patients are known to harbor significantly higher numbers of CD28 null T cells in comparison with patients who have stable angina (SA) and healthy subjects. 8,13 Importantly, Background-The number of CD4 + CD28 null (CD28 null ) T cells, a unique subset of T lymphocytes with proinflammatory and cell-lytic phenotype, increases markedly in patients with acute coronary syndrome (ACS). ACS patients harboring high numbers of CD28 null T cells have increased risk of recurrent severe acute coronary events and unfavorable prognosis. The mechanisms that govern the increase in CD28 null T cells in ACS remain elusive. We investigated whether apoptosis pathways regulating T-cell homeostasis are perturbed in CD28 null T cells in ACS. Methods and Results-We found that CD28null T cells in ACS were resistant to apoptosis induction...

Tumour cells are able to evade the immune system by using several 'escape mechanisms'. Downregulation of molecules involved in the processing and presentation of self-antigens has been reported. However, these adaptations have not been compared in metastases in different anatomical locations but derived from a single patient. We investigated three melanoma cell lines--MJT1 from the parietal lobe of the brain, MJT3 from the cerebellum and MJT5 from the left side of the neck--established from biopsies excised from a 45 year old female patient. Although human leukocyte antigen (HLA) class I was detected in all three cell lines by flow cytometry using an anti-HLA monomorphic antibody, further serological analysis demonstrated HLA B38 loss in all three cell lines, HLA B7 downregulation in MJT5 (skin metastases) and B7 loss in MJT3 and MJT1 (brain metastases) compared with the HLA type of the patient's normal autologous lymphocytes. Interferon-gamma (IFNgamma) treatment increased the expression of HLA class I and transporters associated with antigen processing 1 (TAP1) in all three cell lines. De novo HLA class II molecule expression was observed after IFNgamma treatment in MJT3 and MJT5. Western blot and reverse transcription-polymerase chain reaction results revealed heterogeneity of melanoma-associated antigen (MAA) expression in the cell lines: MJT3 cells expressed higher levels of MAAs than the other two cell lines. In conclusion, this study has demonstrated that three metastatic lesions from a single patient can have differential expression of molecules involved in antigen processing (TAP1) and presentation (HLA I and II), but that expression of these molecules is modulated by IFNgamma to a similar degree in all cell lines. In contrast, the downregulation of expression of specific MAAs between the three cell lines was unaffected by the addition of IFNgamma.

Dendritic cells (DCs) have the ability to generate peptide epitopes for MHC class I molecules derived from apoptotic tumour cells for direct recognition by cytotoxic T cells. This function has lead to DCs being used in vaccine strategies. In this study, we investigate the effect of inducing apoptosis in tumour cell lines using IFN-γ and poly(I:C), the subsequent maturation of the endocytosing DC and its ability to direct the resulting T cell response. We show that uptake of poly(I:C)-induced apoptotic tumour cells leads to DC maturation and activation with a Th1 cell polarising capacity. In contrast, these effects are not seen by DCs loaded with γ-irradiated apoptotic tumour cells. We propose that the manner in which tumour cells are induced to die can have a profound effect on the endocytosing DC and the resulting T cell response.

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