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Key Points Co-stimulatory and co-inhibitory molecules are cell surface receptors and ligands that are classified into various families on the basis of their structure and functions. After interaction with their specific ligands or counter-receptors that positively and negatively regulate T cell function, co-signalling receptors trigger biochemical signals in T cells. Multiple co-stimulatory and co-inhibitory receptors are expressed differentially during specific phases of T cell differentiation and on specific subsets of T cells to direct T cell regulation and function. Co-stimulatory and co-inhibitory molecules constitute important targets for immune modulation and the treatment of human diseases. The central role of co-stimulatory and co-inhibitory receptors in T cell biology has been proven by the effective therapeutic targeting of some of these molecules. However, the molecular aspects of T cell co-stimulation and co-inhibition are far from being fully understood. Here, the authors discuss emerging concepts in T cell co-signalling. Co-stimulatory and co-inhibitory receptors have a pivotal role in T cell biology, as they determine the functional outcome of T cell receptor (TCR) signalling. The classic definition of T cell co-stimulation continues to evolve through the identification of new co-stimulatory and co-inhibitory receptors, the biochemical characterization of their downstream signalling events and the delineation of their immunological functions. Notably, it has been recently appreciated that co-stimulatory and co-inhibitory receptors display great diversity in expression, structure and function, and that their functions are largely context dependent. Here, we focus on some of these emerging concepts and review the mechanisms through which T cell activation, differentiation and function is controlled by co-stimulatory and co-inhibitory receptors.

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM ( TNFRSF14 ) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA–HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier. Here the authors show that BTLA on effector T cells interacts with HVEM on other immunosuppressive cells in the tumor microenvironment. The authors also present evidence that overcoming this checkpoint can ehance CAR T functionality.

BTLA (B- and T-lymphocyte attenuator) is a prominent co-receptor that is structurally and functionally related to CTLA-4 and PD-1. In T cells, BTLA inhibits TCR-mediated activation. In B cells, roles and functions of BTLA are still poorly understood and have never been studied in the context of B cells activated by CpG via TLR9. In this study, we evaluated the expression of BTLA depending on activation and differentiation of human B cell subsets in peripheral blood and lymph nodes. Stimulation with CpG upregulated BTLA, but not its ligand: herpes virus entry mediator (HVEM), on B cells in vitro and sustained its expression in vivo in melanoma patients after vaccination. Upon ligation with HVEM, BTLA inhibited CpG-mediated B cell functions (proliferation, cytokine production, and upregulation of co-stimulatory molecules), which was reversed by blocking BTLA/HVEM interactions. Interestingly, chemokine secretion (IL-8 and MIP1β) was not affected by BTLA/HVEM ligation, suggesting that BTLA-mediated inhibition is selective for some but not all B cell functions. We conclude that BTLA is an important immune checkpoint for B cells, as similarly known for T cells.

The TNF receptor HVEM is shown to control the innate immune response to pathogenic bacteria by regulating mucosal epithelial cells in the intestine and lung. TNF receptors and antibacterial defence The tumour-necrosis-factor receptor HVEM is shown to control the innate immune response to pathogenic bacteria by mucosal epithelial cells in the intestine and lungs. Engagement of HVEM activates Stat3 and leads to production of antimicrobial peptides, chemokines and inflammatory cytokines. Mice deficient in HVEM (herpes virus entry mediator, also called TNFSFR 14) are highly susceptible to intestinal infection with Citrobacter rodentium , a model for the enteropathogenic Escherichia coli infection, and to airway infection by Streptococcus pneumoniae . The authors suggest that HVEM may be a master orchestrator of intestinal and lung epithelial immune responses to bacteria, and that therapeutic targeting of HVEM with agonists could stimulate host defences. The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response 1 . HVEM was recently reported as a colitis risk locus in patients 2 , and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM 3 , but its mechanism of action in the mucosal immune system was unknown. Here we report an important role for epithelial HVEM in innate mucosal defence against pathogenic bacteria. HVEM enhances immune responses by NF-κB-inducing kinase-dependent Stat3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection 4 , 5 , 6 , a mouse model for enteropathogenic Escherichia coli infection, Hvem − / − mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens and increased mortality. We identified the immunoglobulin superfamily molecule CD160 (refs 7 and 8 ), expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection 9 , HVEM is also required for host defence. Our results pinpoint HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicates that targeting HVEM with agonists could improve host defence.

The development of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is driven by chronic inflammatory responses and acquired genetic changes. To investigate its genetic bases, we performed targeted sequencing of 93 genes in 131 MALT lymphomas including 76 from the thyroid. We found frequent deleterious mutations of TET2 (86%), CD274 (53%), TNFRSF14 (53%), and TNFAIP3 (30%) in thyroid MALT lymphoma. CD274 was also frequently deleted, together with mutation seen in 68% of cases. There was a significant association between CD274 mutation/deletion and TNFRSF14 mutation ( p  = 0.001). CD274 (PD-L1) and TNFRSF14 are ligands for the co-inhibitory receptor PD1 and BTLA on T-helper cells, respectively, their inactivation may free T-cell activities, promoting their help to malignant B-cells. In support of this, both the proportion of activated T-cells (CD4+CD69+/CD4+) within the proximity of malignant B-cells, and the level of transformed blasts were significantly higher in cases with CD274 / TNFRSF14 genetic abnormalities than those without these changes. Both CD274 and TNFRSF14 genetic changes were significantly associated with Hashimoto’s thyroiditis ( p  = 0.01, p  = 0.04, respectively), and CD274 mutation/deletion additionally associated with increased erythrocyte sedimentation rate ( p  = 0.0001). In conclusion, CD274 / TNFRSF14 inactivation in thyroid MALT lymphoma B-cells may deregulate their interaction with T-cells, promoting co-stimulations and impairing peripheral tolerance.

Inflammatory Bowel Disease (IBD), encompassing Crohn’s disease and ulcerative colitis, is an umbrella term used to describe a group of autoimmune conditions characterized by chronic, relapsing inflammation of the gastrointestinal tract. The tumour necrosis factor superfamily member 14 (TNFSF14), also known as LIGHT, is a pleiotropic cytokine with diverse roles in immune regulation. Here, we review the multifaceted involvement of LIGHT in intestinal inflammation, particularly its dual capacity to both promote immune activation and facilitate inflammation resolution in the context of IBD. We explore the molecular mechanisms of LIGHT signalling through its receptors, Herpes Virus Entry Mediator (HVEM) and Lymphotoxin-β Receptor (LTβR), and how these distinct interactions dictate its pro-inflammatory or regulatory functions. Finally, we review the therapeutic potential of targeting this pathway, highlighting the results of recent clinical trials and exploring future strategies aimed at restoring immune homeostasis in patients with IBD.

One of the major current trends in cancer immunotherapy is the blockade of immune checkpoint proteins that negatively regulate the immune response. This has been achieved through antibodies blocking PD-1/PD-L1 and CTLA-4/CD80/CD86 interactions. Such antibodies have revolutionized oncological therapy and shown a new way to fight cancer. Additional (negative) immune checkpoints are also promising targets in cancer therapy and there is a demand for inhibitors for these molecules. Our studies are focused on BTLA/HVEM complex, which inhibits T-cell proliferation and cytokine production and therefore has great potential as a new target for cancer treatment. The goal of the presented studies was the design and synthesis of compounds able to block BTLA/HVEM interactions. For that purpose, the N-terminal fragment of glycoprotein D (gD), which interacts with HVEM, was used. Based on the crystal structure of the gD/HVEM complex and MM/GBSA analysis performed on it, several peptides were designed and synthesized as potential inhibitors of the BTLA/HVEM interaction. Affinity tests, ELISA tests, and cellular-based reporter assays were performed on these compounds to check their ability to bind to HVEM and to inhibit BTLA/HVEM complex formation. For leading peptides candidates, all-atom and subsequent docking simulations with a coarse-grained force field were performed to determine their binding modes. To further evaluate their potential as drug candidates, their stability in plasma and their cytotoxicity effects on PBMCs were assessed. Our data indicate that the peptide gD(1-36)(K10C-T29C) is the best candidate as a future drug. It interacts with HVEM protein, blocks the BTLA/HVEM interaction, and is nontoxic to cells. The present study provides a new perspective on the development of BTLA/HVEM inhibitors that disrupt protein interactions.

Improving chimeric antigen receptor (CAR)-T cell therapeutic outcomes and expanding its applicability to solid tumors requires further refinement of CAR-T cells. We previously reported that CAR-T cells bearing a herpes virus entry mediator (HVEM)-derived co-stimulatory signal domain (CSSD) (HVEM-CAR-T cells) exhibit superior functions and characteristics. Here, we conducted comparative analyses to evaluate the impact of different CSSDs on CAR-T cell exhaustion. The results indicated that HVEM-CAR-T cells had significantly lower frequencies of exhausted cells and exhibited the highest proliferation rates upon antigenic stimulation. Furthermore, proliferation inhibition by programmed cell death ligand 1 was stronger in CAR-T cells bearing CD28-derived CSSD (CD28-CAR-T cells) whereas it was weaker in HVEM-CAR-T. Additionally, HVEM-CAR-T cells maintained a low exhaustion level even after antigen-dependent proliferation and exhibited potent killing activities, suggesting that HVEM-CAR-T cells might be less prone to early exhaustion. Analysis of CAR localization on the cell surface revealed that CAR formed clusters in CD28-CAR-T cells whereas uniformly distributed in HVEM-CAR-T cells. Analysis of CD3ζ phosphorylation indicated that CAR-dependent tonic signals were strongly sustained in CD28-CAR-T cells whereas they were significantly weaker in HVEM-CAR-T cells. Collectively, these results suggest that the HVEM-derived CSSD is useful for generating CAR-T cells with exhaustion-resistant properties, which could be effective against solid tumors.

B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor that is expressed by lymphoid cells and regulates the immune response. Consistent with an inhibitory role for BTLA, the disease is exacerbated in BTLA-deficient lupus mice. We recently demonstrated that the BTLA pathway is altered in CD4 + T cells from lupus patients. In the present work, we aimed at delineating the expression pattern of BTLA on CD4 + T cell subsets suspected to play a key role in lupus pathogenesis, such as circulating follicular helper T cells (cT FH ) and regulatory T cells (Tregs). We did not detect significant ex vivo variations of BTLA expression on total CD4 + T cells (naive and memory), cT FH or T FH subsets between lupus patients and healthy controls. However, we interestingly observed that BTLA expression is significantly increased on activated Tregs, but not resting Tregs, from lupus patients, especially those displaying an active disease. Moreover, it correlates with the diminution of the Tregs frequency observed in these patients. We also showed that both BTLA mRNA and protein expression remain low after TCR stimulation of activated Tregs sorted from healthy donors and evidenced a similar dynamic of BTLA and HVEM expression profile by human Tregs and effector CD4 + T cells upon T cell activation than the one previously described in mice. Finally, we observed that the HVEM/BTLA ratio is significantly lower in Tregs from lupus patients compared to healthy controls, whereas ex vivo effector CD4 + T cells express higher BTLA levels. Our data suggest that an altered expression of BTLA and HVEM could be involved in an impaired regulation of autoreactive T cells in lupus. These results provide a better understanding of the BTLA involvement in lupus pathogenesis and confirm that BTLA should be considered as an interesting target for the development of new therapeutic strategies.

The pathogenesis of psoriasis is associated with abnormalities in immune pathways. HVEM is known as a receptor of LIGHT (homologous to lymphotoxins, inducible, and competes with HSV glycoprotein D), which is a newly identified member of the TNF superfamily. The expression of HVEM and LTBR (another LIGHT receptor) has been found to be increased in the skin of psoriasis patients. This indicates the potential role of LIGHT and its receptors in the pathogenesis of psoriasis. Therefore, the objective of this study was to examine the effect of LIGHT on keratinocyte proliferation and its therapeutic potential in the treatment of psoriasis. We used immunohistochemistry to examine their expression in psoriasis-affected and normal tissue samples. We treated cells of the keratinocyte cell line HaCat with LIGHT protein, anti-HVEM and anti-LTβR antibodies, HVEM interference and LTβR interference RNA vectors, and NF-κB and JNK/AP-1 inhibitors at various concentrations and for various times, separately or simultaneously. The expression of NF-κB was examined by immunofluorescence staining, and the expression of inflammatory proteins was measured with ELISA. Further, the viability of HaCat cells was examined with a CCK-8 kit. In addition, flow cytometry was used to detect the expression of HVEM and LTBR on HaCat cells. We found that LIGHT treatment of HaCat cells promoted the nuclear translocation of NF-κB. Further, the expression of p-c-Jun, IL-6, IL-8, PGI2, and PTGS2 was increased in response to LIGHT treatment, but the expression of these factors was decreased when the LIGHT receptors were blocked or NF-κB and JNK/AP-1 expression was inhibited. We also found that the viability of HaCat cells was consistent with the expression of pro-inflammatory factors. The present findings indicate that the JNK/AP-1-HVEM-LIGHT pathway played a role in the viability of human keratinocytes and the expression of IL-6, IL-8, PGI2, and PTGS2. Thus, the JNK/AP-1-HVEM-LIGHT pathway might be a potential target for the treatment of psoriasis.