La metodologia laboratoriale per la formazione degli insegnanti di sostegno

This work aims to define a series of pedagogical principles and reference strategies for workshopin the university environment for teachers specializing in the course for didactic support. Theseprinciples and strategies have been identified on the basis of the work of conducting a laboratorypath entrusted to us in recent years by the Roma Tre University. In this work our previous experiencesof training in the informal field have been brought together.The reflection, after historically contextualizing places and times of this laboratory experience,leads to trace the pedagogical matrices of six reference principles: 1) active education, 2) respect,3) functional learning group, 4) educational experience, 5) integrated training, 6) reflection onexperience.The definition of these principles, accompanied by some examples that are put into practice, canserve as a reference for other university laboratory courses as well as for inclusive laboratoryteaching in the school environment

p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells

The induction of cellular senescence is an important mechanism by which p53 suppresses tumorigenesis. Using a mouse model of liver carcinoma, where cellular senescence is triggered in vivo by inducible p53 expression, we demonstrated that NK cells participate in the elimination of senescent tumors. The elimination of senescent tumor cells is dependent on NKG2D. Interestingly, p53 restoration neither increases ligand expression nor increases the sensitivity to lysis by NK cells. Instead, p53 restoration caused tumor cells to secrete various chemokines with the potential to recruit NK cells. Antibody-mediated neutralization of CCL2, but not CCL3, CCL4 or CCL5, prevented NK cell recruitment to the senescent tumors and reduced their elimination. Our findings suggest that elimination of senescent tumors by NK cells occurs as a result of the cooperation of signals associated with p53 expression or senescence, which regulate NK cell recruitment, and other signals that induce NKG2D ligand expression on tumor cells

Cytokine therapy restores antitumor responses of NK cells rendered anergic in MHC I-deficient tumors.

Recent extraordinary advances in cancer immunotherapy rely primarily on marshaling T cell responses. Here we discuss how NK cell responses can be amplified. We find that MHC I-deficient tumors induce anergy of NK cells but that cytokine therapy restores NK cell activity and increases the survival of mice bearing MHC I-deficient tumors

Cytokine therapy restores antitumor responses of NK cells rendered anergic in MHC I-deficient tumors.

Recent extraordinary advances in cancer immunotherapy rely primarily on marshaling T cell responses. Here we discuss how NK cell responses can be amplified. We find that MHC I-deficient tumors induce anergy of NK cells but that cytokine therapy restores NK cell activity and increases the survival of mice bearing MHC I-deficient tumors

NK cell self tolerance, responsiveness and missing self recognition.

Natural killer (NK) cells represent a first line of defense against pathogens and tumor cells. The activation of NK cells is regulated by the integration of signals deriving from activating and inhibitory receptors expressed on their surface. However, different NK cells respond differently to the same stimulus, be it target cells or agents that crosslink activating receptors. The processes that determine the level of NK cell responsiveness have been referred to collectively as NK cell education. NK cell education plays an important role in steady state conditions, where potentially auto-reactive NK cells are rendered tolerant to the surrounding environment. According to the "tuning" concept, the responsiveness of each NK cell is quantitatively adjusted to ensure self tolerance while at the same time ensuring useful reactivity against potential threats. MHC-specific inhibitory receptors displayed by NK cells play a major role in tuning NK cell responsiveness, but recent studies indicate that signaling from activating receptors is also important, suggesting that the critical determinant is an integrated signal from both types of receptors. An important and still unresolved question is whether NK cell education involves interactions with a specific cell population in the environment. Whether hematopoietic and/or non-hematopoietic cells play a role is still under debate. Recent results demonstrated that NK cell tuning exhibits plasticity in steady state conditions, meaning that it can be re-set if the MHC environment changes. Other evidence suggests, however, that inflammatory conditions accompanying infections may favor high responsiveness, indicating that inflammatory agents can over-ride the natural tendency of NK cells to adjust to the steady state environment. These findings raise many questions such as whether viruses and tumor cells manipulate NK cell responsiveness to evade immune-recognition. As knowledge of the underlying processes grows, the possibility of modulating NK cell responsiveness for therapeutic purposes is becoming increasingly attractive, and is now under serious investigation in clinical studies

Detuning CD8+ T lymphocytes by down-regulation of the activating receptor NKG2D: role of NKG2D ligands released by activated T cells.

NKG2D is an activating receptor expressed on CD8(+)alpha beta(+) T cells, alpha beta(+) T cells, natural killer (NK) cells, and some CD4(+) T cells. For a long time, the interaction of NKG2D with its ligands (NKG2DLs) MICA, MICB, and ULBP1-3 has been considered a mechanism for recognition and elimination of tumor, infected, or otherwise "stressed" cells. However, a new role for NKG2D as an immunoregulatory receptor is emerging. Here, we show that NKG2D is strongly down-modulated on antigen-activated CD8(+) T cells but only if CD4(+) T cells are present. Down-modulation was caused by soluble factors produced by CD4(+) T cells, and in particular soluble NKG2DLs were found in the supernatants of antigen-activated T-cell cultures. MICB was the ligand released at higher levels when CD4(+) T cells were present in the cell cultures, suggesting that it could be the major player of NKG2D down-modulation. CD8(+) T cells expressing low levels of NKG2D had impaired effector functions, as evaluated by proliferation, cytokine production, and cytotoxicity assays after combined triggering of NKG2D and TCR-CD3 complex. These findings show that activated CD4(+) T cells expressing NKG2DLs can efficiently prevent NKG2D-mediated CD8(+) T-cell functions, and suggest that the NKG2D/NKG2DL interaction can regulate immune responses. (Blood. 2009; 113: 2955-2964