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.
Highlights
Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses
Signaling complexes composed of CARD11, BCL10, and MALT1 (CBM complexes) mediate T cell receptor (TCR)-induced canonical activation of nuclear factor-κB (NF-κB) transcription factors in conventional T cells[7], and recent studies highlighted crucial cell-intrinsic roles of canonical NF-κB
In Bcl10fl/fl;CD4-Cre offspring Bcl[10] is deleted at the double-positive stage of thymic T cell development, leading to BCL10 deficiency in peripheral T cells and severe reductions in the number of FoxP3+ Tregs (Supplementary Fig. 1c–e), demonstrating that the known essential functions for BCL10 signaling for early Treg development are T cell lineage intrinsic
Summary
Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses. Signaling complexes composed of CARD11, BCL10, and MALT1 (CBM complexes) mediate TCR-induced canonical activation of nuclear factor-κB (NF-κB) transcription factors in conventional T cells[7], and recent studies highlighted crucial cell-intrinsic roles of canonical NF-κB signaling in Treg development and function for immune homeostasis[8,9,10,11]. The activated catalytic subunit IKK2 phosphorylates inhibitory IκB proteins to induce their proteolytic degradation, which allows the nuclear translocation of the canonical NF-κB subunits p65 and c-Rel to activate gene transcription[7] While this pathway is essential for NF-κB activation after cognate antigen recognition, inflammatory cytokines can engage IKK2 via alternative signalosomes to activate NF-κB even in the absence of the CBM complex in T cells[13,14,15,16]. Our study defines context-specific functions of the CBM complex for Treg differentiation and immune suppression, and provides preclinical evidence that may encourage the exploitation of MALT1 inhibitors in immune oncology
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