CARMA1 Regulation of Regulatory T Cell Development Involves Modulation of Interleukin-2 Receptor Signaling

Abstract

T cell receptor-stimulated NF-B activation requires CARMA1 and is negatively regulated by the deubiquitinase CYLD. Recent studies suggest that CARMA1 regulates regulatory T cell (Treg) development, although the role of NF-B in this event is incompletely understood. We show that CYLD deficiency causes constitutive NF-B activation in thymocytes, which is associated with enhanced frequency of Treg cells. The NF-B activation in CYLDdeficient thymocytes is independent of CARMA1, because the NF-B activation was also detected in CYLD/CARMA1 double knock-out thymocytes. Interestingly, although loss of CYLD causes NF-B activation in the CARMA1-deficient thymocytes, the CYLD deficiency fails to rescue the defect of CARMA1 knock-out mice in Treg development. Furthermore, inhibition of canonical NF-B by an IB␣ transgene only partially inhibits Treg development. We demonstrate that CARMA1 regulates IL-2 receptor signaling and controls the IL-2-stimulated maturation of Treg precursors to mature Tregs. These results suggest that the role of CARMA1 in Treg regulation involves both NF-B activation and IL-2 receptor signaling.

Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects

“…Thus reduced IL-2 production and IL-2 receptor expression might contribute to Treg cell deficiency in human subjects in addition to the previously demonstrated direct role of CARD11 in IL-2 receptor signaling. 23 IFN-g production was more strongly affected than IL-4 production in the T cells of our patient. This is in contrast to recent reports in mice demonstrating a crucial role of CARD11 in T H 2 cell differentiation.…”

“…20,21 The differentiation and maintenance of Treg cells depend on proper IL-2 signals. 22,23 We could demonstrate that CARD11-deficient T cells did not produce normal amounts of IL-2 and upregulation of the IL-2 receptor a chain (CD25) after TCR stimulation was diminished. Thus reduced IL-2 production and IL-2 receptor expression might contribute to Treg cell deficiency in human subjects in addition to the previously demonstrated direct role of CARD11 in IL-2 receptor signaling.…”

Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice

“…This observation could be due to age differences of the mice, as Treg cell numbers significantly increase with age [64], [65]. Moderately reduced thymic but unaltered peripheral frequencies of Treg cells have also been described for IκBαΔNTg mice [62] expressing a truncated form of IκBα, which is refractory to signal-induced degradation [59], [66]. Total CD4 + T cell and Treg cell numbers were markedly decreased in the spleens of IκBαΔNTg mice [66].…”

“…Consistently, we observed a prominent loss of peripheral CD4 + and even more pronounced CD8 + T lymphocytes in IκBα-SR Tg mice ( Figure 1C , upper panel). Of note, the frequency of CD25 + Foxp3 − CD4SP thymocytes, a subpopulation which is enriched in cytokine-dependent Treg precursor cells [38], [39], [59], was markedly reduced in IκBα-SR Tg mice ( Figure 1A , lower panel). The frequencies, as well as absolute cell numbers of mature thymic CD25 + Foxp3 + CD4SP Treg cells were also significantly diminished compared to wild-type controls ( Figure 1A , lower panel, B ).…”

T Cell Activation Threshold Regulated by E3 Ubiquitin Ligase Cbl-b Determines Fate of Inducible Regulatory T Cells

“…Recent studies suggest that CARMA-1, a critical molecule involved in TCR-mediated NF-κB activation, is required for thymic but not peripheral Treg development (26-28). To test whether NF-κB signaling is involved in the regulation of iTreg generation controlled by Cbl-b, we treated naïve CD4 + CD25 − T cells from Cbl-b −/− mice with a NF-κB specific inhibitor.…”