Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells

Marc Rosenbaum, Andreas Gewies, Konstanze Pechloff, Christoph Heuser, Thomas Engleitner, Torben Gehring, Lara Hartjes, Sabrina Krebs, Daniel Krappmann, Mark Kriegsmann, Wilko Weichert, Roland Rad, Christian Kurts and Jürgen Ruland ()
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Marc Rosenbaum: Technical University of Munich
Andreas Gewies: Technical University of Munich
Konstanze Pechloff: Technical University of Munich
Christoph Heuser: Technical University of Munich
Thomas Engleitner: Technical University of Munich
Torben Gehring: German Research Center for Environmental Health
Lara Hartjes: Technical University of Munich
Sabrina Krebs: Technical University of Munich
Daniel Krappmann: German Research Center for Environmental Health
Mark Kriegsmann: University Hospital Heidelberg
Wilko Weichert: Technical University of Munich
Roland Rad: Technical University of Munich
Christian Kurts: Rheinische-Friedrichs-Wilhelms University of Bonn
Jürgen Ruland: Technical University of Munich

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses. Their development and suppressive functions are controlled by the T cell receptor (TCR), but the TCR signaling mechanisms that mediate these effects remain ill-defined. Here we show that CARD11-BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-κB activation in Tregs and controls the conversion of resting Tregs to effector Tregs under homeostatic conditions. However, in inflammatory milieus, cytokines can bypass the CBM requirement for this differentiation step. By contrast, CBM signaling, in a MALT1 protease-dependent manner, is essential for mediating the suppressive function of Tregs. In malignant melanoma models, acute genetic blockade of BCL10 signaling selectively in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses. Together, our data uncover a segregation of Treg differentiation and suppressive function at the CBM complex level, and provide a rationale to explore MALT1 inhibitors for cancer immunotherapy.

Date: 2019
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DOI: 10.1038/s41467-019-10203-2

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