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. Author manuscript; available in PMC: 2023 May 1.
Published in final edited form as: Adv Biol Regul. 2022 Feb 26;84:100890. doi: 10.1016/j.jbior.2022.100890

CARD11 Signaling in Regulatory T Cell Development and Function

Nicole M Carter 1, Joel L Pomerantz 1,*
PMCID: PMC9149070  NIHMSID: NIHMS1786104  PMID: 35255409

Abstract

Regulatory T cells (Tregs) are a critical subset of CD4 T cells that modulate the immune response to prevent autoimmunity and chronic inflammation. CARD11, a signaling hub and scaffold protein that links antigen receptor engagement to activation of NF-κB and other downstream signaling pathways, is essential for the development and function of thymic Tregs. Mouse models with deficiencies in CARD11 and CARD11-associated signaling components generally have Treg defects, but some mouse models develop overt autoimmunity and inflammatory disease whereas others do not. Inhibition of CARD11 signaling in Tregs within the tumor microenvironment can potentially promote anti-tumor immunity. In this review, we summarize evidence for the involvement of CARD11 signaling in Treg development and function and discuss key unanswered questions and future research opportunities.

Introduction

Precise control of the immune system is critical for fighting off pathogens while preventing autoimmunity and chronic inflammation. Regulatory T cells (Tregs) are a subset of CD4 T cells that modulate the immune response through diverse mechanisms, including secretion of anti-inflammatory cytokines, inhibition of antigen presentation, perforin-granzyme cytolysis of effector immune cells, and engagement of inhibitory immunoreceptors (Shevyrev and Tereshchenko, 2020). Tregs can either develop in the thymus (“natural” or nTregs) or can be induced in the periphery from conventional CD4 T cells (“induced” or iTregs) (Schmitt and Williams, 2013). The Treg lineage is marked by expression of the transcription factor FOXP3, and FOXP3 deficiency in humans and mice results in severe and fatal multi-organ inflammatory disease (Zheng and Rudensky, 2007). CARD11 is a signaling hub and scaffold protein that links B and T cell receptor engagement to activation of the NF-κB, JNK, mTOR, and AKT signaling pathways (Bedsaul et al., 2018; Wei et al., 2019). Upon antigen receptor engagement, CARD11 undergoes a conformational change and binds an array of cofactors, which act as both positive and negative regulators of downstream signaling (Figure 1). While CARD11 is perhaps best known for its roles in effector lymphocyte activation, CARD11 and its cofactors also play important roles in the development and function of Tregs. Herein, we review current knowledge of CARD11 signaling in Treg development and function and highlight exciting opportunities for future research.

Figure 1.

Figure 1.

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Schematic role of CARD11 and associated factors downstream of TCR engagement in Tregs. TCR triggering leads to the opening of CARD11 from an inactive to an active state, which is thought to be dependent in part on PKCθ-mediated phosphorylation of the Inhibitory Domain (ID). Following opening, a variety of signaling cofactors associate with CARD11, including Bcl10, MALT1, TAK1, and others. The CARD11-nucleated complex signals to NF-κB, mTORC1, and JNK2, and may regulate Treg development and activity through AKT-FOXO1 and other pathways yet to be identified.

CARD11 Mouse Models

CARD11-mutant and -deficient mouse models have yielded useful knowledge on the importance of CARD11 signaling in Tregs. Mice with complete loss of CARD11 lack thymic Tregs but have normal development of conventional CD4 and CD8 T cells (Barnes et al., 2009; Medoff et al., 2009; Molinero et al., 2009; Policheni et al., 2019). The requirement for CARD11 in nTreg development is cell-intrinsic, and CARD11 is necessary for the development of Treg precursor populations in the thymus (Barnes et al., 2009; Molinero et al., 2009). Because CARD11 is necessary for NF-κB activation downstream of TCR engagement, CARD11-deficient mice are immunodeficient and may not experience autoimmunity or inflammatory disease despite their lack of Tregs, although Policheni et al. reported dermatitis and elevated serum IgE in their CARD11-deficient mouse model. “Unmodulated” mice, which are homozygous for a hypomorphic allele (L298Q) that reduces but does not eliminate NF-κB activation downstream of T cell receptor (TCR)/CD28 costimulation, have a partial Treg defect that results in Th2 expansion, elevated plasma IgE levels, and dermatitis (Altin et al., 2011). Th2 expansion and dermatitis in these mice can be rescued by adoptive transfer of WT Tregs. Salisbury and colleagues reported two additional EMS-generated hypomorphic CARD11 alleles (I79M and L95Q), both of which impair CARD11 binding to its cofactor Bcl10 downstream of T cell stimulation (Salisbury et al., 2014) (Figure 1). Mice homozygous for these alleles have reduced Tregs and Treg precursors in the thymus but do not develop clear signs of autoimmunity or dermatitis, and the percentage of activated CD4 and CD8 T cells in these mice is not significantly higher than that in WT mice. Mice heterozygous for the hypomorphic I79M and L95Q alleles also have intermediate defects in thymic Treg levels. Our group recently described a CARD11 dominant negative mouse model (R30W), which is profoundly immunodeficient and has severe Treg defects in the spleen and thymus (Hutcherson et al., 2021). The R30W mutation prevents the TCR-induced opening of CARD11 oligomers composed of mixed wild type:mutant subunits in heterozygous cells (Bedsaul et al., 2022; Hutcherson et al., 2021). Like the I79M and L295Q mouse models, R30W mice do not exhibit clear autoimmunity or Th2 expansion, although there is an age-dependent elevated IgE phenotype with incomplete penetrance. In addition to its roles in Treg development, CARD11 is also necessary for immune control by mature Tregs. Di Pilato et al. recently reported that mice with conditional deletion of CARD11 in mature Tregs succumb to severe multi-organ Th1-driven inflammatory disease, although mice heterozygous for the conditional allele do not (Di Pilato et al., 2019). Interestingly, the CARD11-knockout Tregs secrete the proinflammatory cytokine IFNɣ. Thus, CARD11 is required for both the development and suppressive function of nTregs, and when CARD11 deficiency in nTregs is not balanced by defects in conventional T cells, this results in immune dysregulation.

Conflicting evidence exists as to whether or not CARD11 is required for iTreg differentiation. Medoff et al. reported a lack of both thymic and peripheral Tregs in CARD11 knockout mice, whereas Barnes et al. reported the presence of peripheral Tregs in their CARD11-deficient mouse model (Barnes et al., 2009; Medoff et al., 2009). Furthermore, Barnes et al. could generate iTregs in vitro from CARD11-deficient CD4+FOXP3− T cells, and these in vitro generated Tregs were functional. Policheni and colleagues also reported the presence of peripheral Tregs in a separate CARD11-deficient mouse model, and when these peripheral Tregs were expanded in vivo with an IL-2:anti-IL-2 complex and then isolated, they could suppress the growth of conventional CD4 T cells, albeit less well than IL-2:anti-IL-2 expanded WT Tregs (Policheni et al., 2019). Similarly, when iTregs were induced in vitro from naïve CD4 T cells with homozygous CARD11 loss-of-function mutations, FOXP3 upregulation was less than that in iTregs from WT precursors (Salisbury et al., 2014). Taken together, these findings suggest that while CARD11 is essential for nTreg development and function, CARD11 is partially but not entirely dispensable for the development and function of iTregs.

Mechanistically, the role of CARD11 in Treg development and function appears to involve NF-κB activation as well as other pathways (Figure 1). FoxP3 is an NF-κB target gene, and expression of constitutively active IKKβ, the kinase that phosphorylates IκBα to allow for NF-κB nuclear translocation downstream of TCR engagement, rescues FOXP3 expression in CARD11-deficient thymocytes (Long et al., 2009). However, deletion of CYLD, which results in constitutive NF-κB activation even in the absence of CARD11, does not rescue the Treg defects observed in CARD11 knockout mice, and inhibition of NF-κB with a non-degradable IκBα transgene causes only a moderate Treg defect (Lee et al., 2010). Likewise, when Di Pilato et al. expressed constitutively active IKKβ in Tregs harboring conditional deletion of CARD11, this did not prolong the mice’s lifespan or reduce IFN-ɣ secretion by the CARD11-KO Tregs (Di Pilato et al., 2019). These findings suggest NF-κB-independent roles for CARD11 in Treg development and function. Lee et al. reported that CARD11-KO Treg precursors have diminished responses in vitro to IL-2, raising the possibility that CARD11 is involved in the IL-2 dependent transition from CD4+CD25+FOXP3− nTreg precursors into CD4+CD25+FOXP3+ Tregs (Lee et al., 2010). On the other hand, Policheni et al. successfully expanded CARD11-deficient iTregs in vivo using an IL-2:anti-IL-2 complex and reported a greater fold increase in Treg levels in CARD11-deficient mice than in WT mice (Policheni et al., 2019). This suggests that the requirement for CARD11 in responses to IL-2 might differ between nTreg and iTreg precursors. CARD11’s role in Treg development and function may also involve the AKT-FOXO1 signaling axis (Figure 1). AKT phosphorylates FOXO1, leading to its degradation and thereby downregulating the expression of FOXO1 target genes. It was recently shown that in B cells, CARD11 negatively regulates AKT activation, and loss of CARD11 results in decreased FOXO1 target gene expression (Wei et al., 2019). AKT activation via PI3K appears to negatively regulate the development of thymic and peripheral Tregs, and FOXO1-dependent transcriptional programs play crucial roles in Treg development and function (Kerdiles et al., 2010; Ouyang et al., 2012; Poli et al., 2020). Therefore, CARD11 may promote Treg development and/or suppressive function by inhibiting the phosphorylation of FOXO1 by AKT. Additional research is needed to confirm that CARD11 negatively regulates AKT signaling to FOXO1 in T cells as it does in B cells. It is also possible that other signaling outputs downstream of CARD11 are necessary for Treg development and function, and a more thorough understanding of CARD11 signaling will help us to better interpret the phenotypes observed in different CARD11 mouse models.

MALT1 Mouse Models

MALT1 is a CARD11 cofactor with dual functions as a scaffold and a protease (Figure 1). MALT1’s scaffold function facilitates interactions required for the downstream activation of IKKβ, and its protease function “fine-tunes” CARD11 signaling to NF-κB by cleaving both activators (HOIL-1L) and repressors (CYLD, A20, REL-B) of the pathway (Juilland and Thome, 2018). Because MALT1 is one of the few CARD11 cofactors with enzymatic activity, extensive work has been done to understand its contributions to the immune response. MALT1-knockout (KO) mice have severe Treg defects and a decreased percentage of activated Tregs that express CTLA-4 (Brüstle et al., 2017; Mc Guire et al., 2013). These Treg defects are balanced by defects in conventional T cell activation, and consequently, MALT1-KO mice do not exhibit overt autoimmunity and are resistant to experimental autoimmune encephalomyelitis (EAE). Brüstle et al. reported that although MALT1-KO mice lack thymic Tregs, they have peripheral Tregs which increase as the mice age. Interestingly, following immunization with MOG peptide to induce EAE, Brüstle et al. reported greater iTreg induction in the central nervous system of MALT1-KO mice than in WT mice, suggesting that MALT1 promotes thymic nTreg differentiation but inhibits peripheral iTreg differentiation. It should be noted that although MALT1-KO mice do not exhibit clear signs of autoimmunity, at least one group has reported dermatitis, Th2 expansion, and elevated serum IgE in aged MALT1-KO mice (Demeyer et al., 2019b). Thus, defects in conventional T cells may not entirely prevent inflammatory disease caused by Treg defects in MALT1-KO mice.

Mouse models harboring catalytically inactive MALT1 have been useful tools for teasing apart MALT1 scaffold and protease activities in Treg development and function. MALT1 protease-deficient (MALT1-PD) mice have reduced Treg percentages in the spleen and lymph nodes and a near-total absence of thymic Tregs, despite little-to-no defect in IκBα phosphorylation and degradation (Bornancin et al., 2015; Gewies et al., 2014; Jaworski et al., 2014). Unlike in MALT1-KO mice, the Treg defects in MALT1-PD mice are not balanced by defects in conventional T cell activation, and MALT1-PD mice experience autoimmunity, Th2 expansion, and severe multi-organ inflammation (Bornancin et al., 2015; Gewies et al., 2014; Jaworski et al., 2014; Yu et al., 2015). The Treg defects observed in MALT1-PD mice are T cell intrinsic, and Treg deficiencies in these mice allow for the expansion of pathogenic, IFNɣ secreting CD4+NRP1+FOXP3− T cells (Demeyer et al., 2019a; Martin et al., 2019). In addition to its roles in Treg development, MALT1 protease activity is also necessary for the suppressive function of mature Tregs. Two groups have reported that mice conditionally expressing catalytically dead MALT1 in mature Tregs experience inflammatory disease, and MALT1-PD Tregs have impaired suppressive function (Cheng et al., 2019; Rosenbaum et al., 2019). Interestingly, conditional deletion of MALT1 in mature Tregs reportedly results in a more severe inflammatory disease state than conditional expression of protease-deficient MALT1 in Tregs, suggesting that MALT1’s scaffold function is also involved in the suppressive activity of mature Tregs (Cheng et al., 2019).

Two non-mutually exclusive mechanisms have been proposed for how MALT1 protease activity might control Treg development and function. Gewies et al. reported that although MALT1-PD T cells have intact IκBα phosphorylation and degradation downstream of TCR stimulation, DNA binding of the NF-κB family transcriptional activators p50 and c-Rel is decreased, whereas DNA binding of the transcriptional repressor REL-B is increased (Gewies et al., 2014). This fine-tuning of NF-κB transcriptional activity may result in altered expression of FoxP3 and/or other genes involved in Treg development and function. In addition to cleaving proteins involved in NF-κB activation, MALT1 also cleaves the mRNA binding proteins Regnase-1, Roquin-1, and Roquin-2, which degrade CTLA-4 mRNA (Jeltsch et al., 2014; Uehata et al., 2013). Therefore, reduced CTLA-4 mRNA levels in MALT1-PD and MALT1-KO T cells may contribute to the Treg phenotypes observed in these mice (Demeyer et al., 2019a; Gewies et al., 2014; Rosenbaum et al., 2019).

Other Signaling Components

Protein Kinase C theta (PKCθ) is a kinase that in T cells is thought to phosphorylate CARD11 downstream of TCR engagement to promote the conversion of CARD11 to an open and active conformation in a step necessary for subsequent cofactor recruitment (Bedsaul et al., 2018) (Figure 1). PKCθ knockout mice have reduced Tregs in the thymus, spleen and lymph nodes and reduced FoxP3 mRNA levels in CD4 T cells; however, PKCθ knockout Tregs inhibit conventional T cell activation and proliferation similarly to WT Tregs (Gupta et al., 2008; Schmidt-Supprian et al., 2004). Bcl10 is an adaptor protein that is necessary for downstream activation of IKKβ in T cells and mediates MALT1 binding to the CARD11 complex (Figure 1). Bcl10 KO mice have reduced splenic and thymic Tregs, and like PKCθ KO mice, FoxP3 mRNA levels in their CD4 T cells are decreased compared to WT T cells (Schmidt-Supprian et al., 2004). Deletion of Bcl10 in mature Tregs also results in lack of suppressive function and autoimmunity, which are not rescued by constitutively active IKKβ (Rosenbaum et al., 2019). The kinase TAK1 is recruited to the activated CARD11 complex and facilitates activation of both the NF-κB and JNK pathways (Lu et al., 2018) (Figure 1). Wan et al. reported that conditional deletion of TAK1 in T cells results in a lack of thymic Tregs, and nearly all peripheral T cells in these mice have an activated/effector phenotype and increased cytokine production (Wan et al., 2006). Mice with conditional deletion of TAK1 in T cells also develop colitis as they age (Sato et al., 2006). Downstream of the CARD11 complex, conditional deletion of IKKβ in T cells results in Treg defects in the spleen, lymph node, and thymus (Schmidt-Supprian et al., 2003). These findings highlight the critical role of CARD11 signaling to NF-κB and other pathways in Treg development and the prevention of autoimmunity. Further interrogation of the different Treg phenotypes observed in mouse models deficient in different CARD11-associated signaling components may advance our understanding of which CARD11-dependent pathways control which stages of Treg development and function.

Patient Findings

Studies of patients with mutations in CARD11 and associated signaling components have provided useful insight to complement findings from mouse models. Two patients were recently reported with complete CARD11 deficiency, both of whom had a lack of detectable blood Tregs (Lu et al., 2021). Surprisingly, in two large studies of individuals with dominant negative CARD11 mutations, most patients had normal Treg levels despite also experiencing atopic disease (Dorjbal et al., 2018; Ma et al., 2017). In an in-depth study of patients with the dominant negative R30W mutation, which causes profound Treg defects in mice, all patients had normal Treg levels, but they experienced atopy and food allergies (Dadi et al., 2018; Hutcherson et al., 2021). The conflicting Treg phenotypes observed in mouse models versus patients with CARD11 dominant negative mutations may reflect differences between species, variation in experimental techniques, or the different antigens encountered by mice and humans living in different environments.

Several studies have reported on Treg defects in patients with MALT1-deficiency. Patients with homozygous mutations resulting in a lack of detectable MALT1 protein have severe Treg defects and suffer from inflammatory disease as well as combined immunodeficiency (Charbit-Henrion et al., 2017; Frizinsky et al., 2019; Punwani et al., 2015). McKinnon et al. reported an additional patient with a homozygous MALT1 mutation that resulted in reduced protein levels and lack of protease activity; this patient had combined immunodeficiency and severe dermatitis, but her Treg levels were normal (McKinnon et al., 2014). Two studies have reported immunodeficiency and severe Treg reductions in patients with null Bcl10 alleles, and the patient described by Torres et al. had inflammatory colitis that was presumably caused by their lack of Tregs (Garcia-Solis et al., 2021; Torres et al., 2014). Future studies of additional patients with mutations in CARD11, MALT1, Bcl10, and other CARD11-associated signaling components will further our knowledge of how CARD11 signaling impacts Treg development and function in humans and how to best treat the immune dysregulation observed in these patients.

Therapeutic Implications

Due to the role of CARD11 signaling in Treg function, targeting CARD11 signaling in the tumor microenvironment may enhance anti-tumor immunity. Di Pilato et al. showed that CARD11 deletion in Tregs or pharmacological inhibition of MALT1 reduces the growth of implanted melanoma tumors in mice, and these effects synergize with anti-PD-1 checkpoint inhibition for even greater tumor control (Di Pilato et al., 2019). Similarly, Rosenbaum et al. showed that conditional deletion of Bcl10 in Tregs or pharmacological inhibition of MALT1 protease reduces the growth of implanted B16F1 tumors, and MALT1 inhibition increases the percentage of IFNɣ-producing CD4 and CD8 T cells in the tumor microenvironment (Rosenbaum et al., 2019). Cheng et al. also reported slower growth of E.G7 tumors in mice conditionally expressing protease-deficient MALT1 in their Tregs as well as reduced Treg infiltration and CD8 exhaustion in the tumor microenvironment (Cheng et al., 2019). Despite these exciting findings from mouse models, there are concerns that long-term MALT1 protease inhibition in patients could result in inflammatory disease similar to what is observed in MALT1-PD mice. In long-term studies of a highly potent MALT1 protease inhibitor (MLT-943), rats had reduced circulating Tregs, systemic T cell activation, elevated IgE, and severe intestinal inflammation after 13 weeks of treatment (Martin et al., 2020). The effects of long-term MLT-943 administration occurred even in rats that were thymectomized prior to treatment, suggesting that MALT1 protease inhibitors affect the development and function of iTregs as well as nTregs. On the other hand, mice treated with a less potent MALT1 inhibitor (mepazine) for up to 24 days following induction of EAE did not show reduced Tregs and had less central nervous system inflammation than vehicle-treated mice (Mc Guire et al., 2014). Additionally, inducible expression of MALT1-PD for up to six months in adult mice reduced Treg levels but did not cause systemic T cell activation, autoimmunity, or severe inflammatory disease (Demeyer et al., 2020). There is also some evidence that potent MALT1 inhibitors targeting both protease and scaffold functions might retain the benefits of MALT1 protease inhibition without inducing inflammatory disease (Dumont et al., 2020). Further research is needed to determine the optimal strategy for inhibiting MALT1 to promote anti-tumor immunity without inducing systemic inflammatory disease.

Future Research Questions

What is the correlation between NF-κB activation and Treg development and function? Canonical NF-κB signaling is necessary for thymic Treg development, and FoxP3 is an NF-κB target gene (Long et al., 2009; Oh et al., 2017). However, constitutively active NF-κB does not rescue all of the Treg phenotypes observed in CARD11-deficient mouse models, and iTregs can develop from CARD11-deficient naïve CD4 T cells despite their impaired NF-κB activation. Furthermore, mice with a non-degradable IκBα transgene, which blocks canonical NF-κB activation, have only moderate defects in thymic Treg levels and normal splenic Treg levels (Lee et al., 2010). Therefore, while NF-κB is clearly important for Treg development and function, other pathways are also likely involved (Figure 1). There also appears to be a difference in the role of NF-κB signaling in the development and function of nTregs versus iTregs. RNA-seq or proteomics analysis of NF-κB signaling intermediates and target gene expression at different stages of nTreg and iTreg development would provide useful insight as to when and how NF-κB is involved.

In addition to MALT1 inhibition, how else might we target CARD11 signaling to promote anti-tumor immunity? Additional studies may identify novel CARD11 cofactors that serve as positive or negative regulators of downstream signaling, and some of these cofactors could be druggable targets. Alternative strategies to target CARD11 signaling in the tumor microenvironment might promote anti-tumor immunity and synergize with checkpoint inhibitor therapy – like what has been observed for MALT1 inhibitors – with fewer long-term safety concerns. It may also be possible to selectively inhibit CARD11 signaling in the tumor microenvironment without affecting systemic CARD11 signaling. Additional research is likely to fine-tune our understanding of CARD11 signaling, which may unveil additional druggable targets and new therapeutic strategies.

In summary, CARD11 and its associated signaling components play crucial roles in the development and function of nTregs, while CARD11 signaling may be less important in iTregs. The importance of CARD11 signaling in Treg development and function appears to involve NF-κB activation as well as additional signaling pathways. Additional research will likely refine the correlation between NF-κB activation and different stages of Treg development and activation. Inhibition of CARD11 signaling in the tumor microenvironment has the exciting potential to promote anti-tumor immunity and to synergize with checkpoint inhibitor therapy, although additional research is needed to refine this strategy to maximize effectiveness and patient safety. Further mechanistic research on the regulation of CARD11 signaling will inform our interpretation of phenotypes in patients and mouse models with deficiencies in CARD11 and its associated signaling components and may inspire novel approaches for targeting CARD11 signaling in patients.

Acknowledgments

This work was supported by National Institutes of Health Grants RO1AI143053, F31CA254167, and T32GM007445.

Footnotes

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Credit Author Statement

Nicole M. Carter: Writing-Original Draft, Reviewing and Editing; Joel L.Pomerantz: Writing-Reviewing and Editing.

The authors declare no conflict of interest.

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