FoxP3 is a member of the forkhead family of transcription factors critically involved in the development and function of CD25
Activin-A is a transforming growth factor- (TGF-) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immuneregulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells (DCs) to stimulate immune responses. Human monocyte-derived DCs IntroductionDendritic cells (DCs) form sentinel networks within the body sampling the microenvironment for pathogens, tissue injury, and inflammation via an array of pattern recognition receptors. [1][2][3] Pathogen encounter induces DC maturation, resulting in profound alterations in DC function. Antigen uptake is reduced, antigen processing is enhanced, and proinflammatory mediators are released. [4][5][6][7][8] The class, magnitude, and timing of cytokine or chemokine release are under exquisite control through both autocrine and paracrine signals as well as the signal strength and magnitude of the initiating stimulus. 8 DC cytokine and chemokine production can be induced by specific classes of stimuli. These include CD40 ligand (CD40L) and pathogen signals, such as toll-like receptor (TLR) agonists (eg, lipopolysaccharide [LPS] or intact bacteria). Appropriate release of cytokines, chemokines, and other soluble mediators by DCs and neighboring cells induces and moderates inflammation, recruits innate effectors, and regulates T-cell functions. [9][10][11][12] Many cytokines/chemokines produced by DCs at the epicenter of infection and inflammation, such as interleukin-6 (IL-6), 13,14 IL-8, 4,15,16 IL-10 17,18 as well as the potent T helper 1 (Th-1) cytokine, 19,20 have pleiotropic effects ranging from enhancing to inhibitory depending on the context and target cell type. However, uncontrolled cytokine/chemokine release within this microenvironment can also result in inappropriate T-and B-cell responses and subsequent immunopathology. [21][22][23] In this regard, the immune system has evolved to coordinately express mediators that attenuate exaggerated or inappropriate responses so as to minimize tissue damage and immunopathology (eg, prostaglandin E 2 (PGE 2 ), adenosine triphosphate (ATP), transforming growth factor- [TGF-]). 24 Activin-A is a homodimer of activin-A subunits and was first described as a reproductive factor that accentuates the release of follicle-stimulating hormone. 25 It is a member of the TGF- superfamily of cytokines and intimately shares with TGF- the Smad intracellular signaling proteins. 26 The signaling, however, occurs through separate and distinct serine threonine kinase receptor subunits, and its release into the circulation during acute systemic inflammation differs from TGF-. 27 Activin-A signals through heteromeric receptor complexes consisting of both type I (ALK 2, 4, or 7) and type II (ActRIIA and ActRIIB) receptors. In addition, it is known to be pivotal in ...
Loss-of-function mutations in the gene coding for perforin (PRF1) markedly reduce the ability of cytotoxic T lymphocytes and natural killer cells to kill target cells, causing immunosuppression and impairing immune regulation. In humans, nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations. The partial inactivation of PRF1 due to mutations that promote protein misfolding or the common hypomorphic allele coding for the A91V substitution have been associated with lymphoid malignancies in childhood and adolescence. To investigate whether PRF1 mutations also predispose adults to cancer, we genotyped 566 individuals diagnosed with melanoma (101), lymphoma (65), colorectal carcinoma (30) or ovarian cancer (370). The frequency of PRF1 genotypes was similar in all disease groups and 424 matched controls, indicating that the PRF1 status is not associated with an increased susceptibility to these malignancies. However, four out of 15 additional individuals diagnosed with melanoma and B-cell lymphoma during their lifetime expressed either PRF1A91V or the rare pathogenic PRF1R28C variant (p = 0.04), and developed melanoma relatively early in life. Both PRF1A91V- and PRF1R28C-expressing lymphocytes exhibited severely impaired but measurable cytotoxic function. Our results suggest that defects in human PRF1 predispose individuals to develop both melanoma and lymphoma. However, these findings require validation in larger patient cohorts.
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