Activation of the T cell-mediated immune response has been associated with changes in the expression of specific microRNAs (miRNAs). However, the role of miRNAs in the development of an effective immune response is just beginning to be explored. This study focuses on the functional role of miR-146a in T lymphocyte-mediated immune response and provides interesting clues on the transcriptional regulation of miR146a during T-cell activation. We show that miR-146a is low in human naive T cells and is abundantly expressed in human memory T cells; consistently, miR-146a is induced in human primary T lymphocytes upon T-cell receptor (TCR) stimulation. Moreover, we identified NF-kB and c-ETS binding sites as required for the induction of miR-146a transcription upon TCR engagement. Our results demonstrate that several signaling pathways, other than inflammation, are influenced by miR-146a. In particular, we provide experimental evidence that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fasassociated death domain (FADD) is a target of miR-146a. Furthermore, miR146a enforced expression impairs both activator protein 1 (AP-1) activity and interleukin-2 (IL-2) production induced by TCR engagement, thus suggesting a role of this miRNA in the modulation of adaptive immunity. (Blood. 2010;115: 265-273) IntroductionDuring adaptive immune response T-cell receptor (TCR) engagement by the antigen triggers a signal cascade, which leads to the activation of 3 main transcription factors: AP-1, NF-kB, and NFAT, critically involved in cytokine production. In particular, these transcription factors regulate the expression of early cytokines, especially interleukin-2 (IL-2), that mediate the lymphocytic "clonal expansion" phase. 1 Once the foreign threat has been overcome and T lymphocytes have served their effector functions, they must be removed. The death of activated lymphocytes serves to limit the immune response by killing cells that are no longer needed or cells that may have developed the potential to recognize and generate a response to selfantigens. Deregulation of apoptotic pathways in T cells may lead to a spectrum of diseases, including autoimmune diseases and proliferative disorders. 2,3 MicroRNAs (miRNAs) recently came into focus as a novel class of posttranscriptional regulatory elements. They are small endogenous noncoding RNAs that repress mRNA translation by base pairing to 3Ј untranslated region (3ЈUTR) of the target genes. In particular, miRNAs are powerful tools that can be promptly expressed by the cell and have the potential to coordinately regulate a large number of different target genes. This suggests that they can be optimal candidates for the control of immune response, a process involving large regulative networks and fine prompt modulation.The first indication that miRNAs are involved in immunity has emerged by studies showing the selective expression of miR-223 in bone marrow and the involvement of miR-223, miR-155, and miR-146a in the differentiation ...

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We found that the proteome of apoptotic T cells includes prominent fragments of cellular proteins generated by caspases and that a high proportion of distinct T cell epitopes in these fragments is recognized by CD8+ T cells during HIV infection. The frequencies of effector CD8+ T cells that are specific for apoptosis-dependent epitopes correlate with the frequency of circulating apoptotic CD4+ T cells in HIV-1-infected individuals. We propose that these self-reactive effector CD8+ T cells may contribute to the systemic immune activation during chronic HIV infection. The caspase-dependent cleavage of proteins associated with apoptotic cells has a key role in the induction of self-reactive CD8+ T cell responses, as the caspase-cleaved fragments are efficiently targeted to the processing machinery and are cross-presented by dendritic cells. These findings demonstrate a previously undescribed role for caspases in immunopathology.

BackgroundIsolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma.Methods and resultsHere, we report the clinical and molecular investigations of two patients with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to novel SDH gene mutations; the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations, while the second patient presented with hypotonia and leukodystrophy with elevated brain succinate demonstrated by MR spectroscopy due to a novel, homozygous p.Asp48Val SDHB mutation. Western blotting and BN-PAGE studies confirmed decreased steady-state levels of the relevant SDH subunits and impairment of complex II assembly. Evidence from yeast complementation studies provided additional support for pathogenicity of the SDHB mutation.ConclusionsOur report represents the first example of SDHB mutation as a cause of inherited mitochondrial respiratory chain disease and extends the SDHA mutation spectrum in patients with isolated complex II deficiency.