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

Nat Commun. 2019 May 28;10(1):2352. doi: 10.1038/s41467-019-10203-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Cell CLL-Lymphoma 10 Protein / immunology*
  • B-Cell CLL-Lymphoma 10 Protein / metabolism
  • CARD Signaling Adaptor Proteins / immunology*
  • CARD Signaling Adaptor Proteins / metabolism
  • Cell Differentiation
  • Cytokines / immunology
  • Melanoma, Experimental
  • Mice
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / immunology*
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / metabolism
  • NF-kappa B / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism


  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CARD Signaling Adaptor Proteins
  • Card11 protein, mouse
  • Cytokines
  • NF-kappa B
  • Receptors, Antigen, T-Cell
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein