MALT1 and Caspase-10 : two cysteine proteases controlling lymphocyte activation

Τ cell activation via the Τ cell receptor (TCR) through antigen recognition is one of the key steps to initiate the adaptive immune response. The mechanisms controlling TCR-induced signaling pathways are the subject of intense research, since deregulated signaling in lymphocytes can lead to immunodeficiency, autoimmunity or lymphomas. In Τ lymphocytes a complex composed of CARMA1, BCL10 and MALT1 has been identified to receive signals from TCR proximal events and to induce further signals crucial for Τ cell activation. MALT1 is scaffold protein and a cysteine protease and both functions have been shown, among other effects, to be crucial to initiate the activation of the transcription factors of the nuclear factor κΒ (NF-κΒ) family after TCR-stimulation. Several proteolytic targets have been described recently and all of them play roles in modulating NF-κΒ activation or other aspects of Τ cell activation. In this study, we describe a novel target of MALT1, Caspase-10. Two isoforms of Caspase-10 are cleaved by MALTI in Τ and Β cells after antigen receptor stimulation. Caspases are a family of cysteine proteases that are known for their roles in cell death and certain immune functions. Caspase-10 has so far only been reported to be involved in the induction of apoptosis. However it is very closely related to the well-characterized Caspase-8 that has been reported to be involved in Τ cell activation. In the present study, we describe a crucial role for Caspase-10, but not Caspase-8, in Τ cell activation after TCR stimulation. Jurkat Τ cells silenced for Caspase-10 expression exhibit a dramatic reduction in IL-2 production following stimulation. The data obtained revealed that this is due to severely reduced activation of activator protein-1 (AP-1), another transcription factor family with key functions in the process of Τ cell activation. We observed strongly reduced expression levels of the AP-1 family member c-Fos after Τ cell stimulation. This transcription factor is expressed upon TCR stimulation and is a crucial component of AP-1 transcription factor dimers required for Τ cell activation. In further analysis, it was shown that this defect is not based on reduced transcription, as the c-Fos mRNA levels are not altered, but rather seems to be caused by a defect in translation or protein stability in the absence of Caspase-10. Furthermore, we report a potential interaction of the c-Fos protein and Caspsae-10. This role of Caspase-10 in AP-1 activation however is independent of its cleavage by MALT1, leaving the role of Caspase-10 cleavage in activated lymphocytes unclear. Taken together, these results give new insights into the complex matter of lymphocyte activation whose understanding is crucial for the development of new drugs modulating the immune response or inhibiting lymphoma progression.

Fiscal Update, March 10, 1998

The Fiscal Division newsletter, published weekly during session and periodically during the interim.

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This contribution introduces Data Envelopment Analysis (DEA), a performance measurement technique. DEA helps decision makers for the following reasons: (1) By calculating an efficiency score, it indicates if a firm is efficient or has capacity for improvement; (2) By setting target values for input and output, it calculates how much input must be decreased or output increased in order to become efficient; (3) By identifying the nature of returns to scale, it indicates if a firm has to decrease or increase its scale (or size) in order to minimise the average total cost; (4) By identifying a set of benchmarks, it specifies which other firms' processes need to be analysed in order to improve its own practices. This contribution presents the essentials about DEA, alongside a case study to intuitively understand its application. It also introduces Win4DEAP, a software package that conducts efficiency analysis based on DEA methodology. The methodical background of DEA is presented for more demanding readers. Finally, four advanced topics of DEA are treated: adjustment to the environment, preferences, sensitivity analysis and time series data.

Fiscal Update, August 10, 1998

The Fiscal Division newsletter, published weekly during session and periodically during the interim.

Fiscal Update, April 10, 2000

The Fiscal Division newsletter, published weekly during session and periodically during the interim.

Fiscal Update, June 10, 2001

The Fiscal Division newsletter, published weekly during session and periodically during the interim.

Fiscal Update, December 10, 2001

The Fiscal Division newsletter, published weekly during session and periodically during the interim.

Fiscal Update, December 10, 2001

The Fiscal Division newsletter, published weekly during session and periodically during the interim.