Current understanding of CTLA-4: from mechanism to autoimmune diseases

Hossen, Md. Munnaf; Ma, Yanbing; Yin, Zhihua; Xia, Yifan; Du, Jing; Huang, Jian; Zou, Linghua; Ye, Zhizhong; Huang, Zhong

doi:10.3389/fimmu.2023.1198365

Cited by 46 publications

(12 citation statements)

References 185 publications

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“…Lastly, for some analyses, we had a moderate to low sample size. Furthermore, we included molecules such as CTLA-4 and LAG-3, which are important for optimal regulation and homeostasis of T cells within the tumor microenvironment [ 92 , 93 ]. Given our focus on oropharyngeal carcinoma, it is important to include gamma delta T cells in our future analyses since these cells defend mucosa from pathogens and maintain homeostasis for further immunoregulatory functions [ 94 ].…”

Section: Discussionmentioning

confidence: 99%

Immune and Microbial Signatures Associated with PD-1 Blockade Sensitivity in a Preclinical Model for HPV+ Oropharyngeal Cancer

Díaz-Rivera,

Rodríguez-Rivera,

Meléndez-Vázquez

et al. 2024

Cancers

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The United States is suffering from an epidemic associated with high-risk strains of the Human Papillomavirus (HPV) predominantly responsible for the development of head and neck squamous cell carcinoma (HNSCC). Treatment with immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand PD-L1 has shown poor efficacy in HNSCC patients, observing only a 20–30% response. Therefore, biological marker identification associated with PD-1 blockade response is important to improve prognosis and define novel therapeutics for HNSCC patients. Therapy response was associated with increased frequencies of activated CD27+T cells, activated CD79a+ B cells, antigen-presenting CD74+ dendritic and B cells, and PD-L1+ and PD-L2+ myeloid-derived suppressor cells (MDSCs). The oral microbiota composition differed significantly in mice bearing tongue tumors and treated with anti-PD-1. A higher abundance of Allobaculum, Blautia, Faecalibacterium, Dorea, or Roseburia was associated with response to the therapy. However, an increase in Enterococcus was attributed to tongue tumor-bearing non-responding mice. Our findings indicate that differences in immune phenotypes, protein expression, and bacterial abundance occur as mice develop tongue tumors and are treated with anti-PD-1. These results may have a clinical impact as specific bacteria and immune phenotype could serve as biomarkers for treatment response in HNSCC.

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Section: Discussionmentioning

confidence: 99%

Immune and Microbial Signatures Associated with PD-1 Blockade Sensitivity in a Preclinical Model for HPV+ Oropharyngeal Cancer

Díaz-Rivera,

Rodríguez-Rivera,

Meléndez-Vázquez

et al. 2024

Cancers

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“…Abatacept (Orencia ® , Bristol Myers Squibb, Princeton, NJ, USA), (CTLA4-Ig) acts as a competitive inhibitor for CD28 situs-binding proteins, causing T-cells to become anergic. Abatacept is currently an approved therapeutic strategy in rheumatoid arthritis and autoimmune disorders [ 62 ].…”

Section: Immunologic Strategies In Vcamentioning

confidence: 99%

Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation?

Grosu-Bularda,

Hodea,

Zamfirescu

et al. 2024

JPM

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The field of transplantation, including the specialized area of vascularized composite allotransplantation (VCA), has been transformed since the first hand transplant in 1998. The major challenge in VCA comes from the need for life-long immunosuppressive therapy due to its non-vital nature and a high rate of systemic complications. Ongoing research is focused on immunosuppressive therapeutic strategies to avoid toxicity and promote donor-specific tolerance. This includes studying the balance between tolerance and effector mechanisms in immune modulation, particularly the role of costimulatory signals in T lymphocyte activation. Costimulatory signals during T cell activation can have either stimulatory or inhibitory effects. Interfering with T cell activation through costimulation blockade strategies shows potential in avoiding rejection and prolonging the survival of transplanted organs. This review paper aims to summarize current data on the immunologic role of costimulatory blockade in the field of transplantation. It focuses on strategies that can be applied in vascularized composite allotransplantation, offering insights into novel methods for enhancing the success and safety of these procedures.

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“…The absence of CTLA-4 disrupts Treg cell function, leading to unchecked proliferation and activation of Tconvs, which can result in autoimmune pathology ( 150 ). Researchers have shown that introducing the extracellular domain of CTLA-4 (cdCTLA-4) into mice lacking CTLA-4 fully restores Treg activity, suggesting that cdCTLA-4 is sufficient to provide inhibitory function ( 151 ). This implies that CTLA-4 function may not necessarily involve a signal transduction process.…”

Section: Co-stimulatory Moleculesmentioning

confidence: 99%

Regulation of Treg cells by cytokine signaling and co-stimulatory molecules

Zong,

Deng,

Chong

2024

Front. Immunol.

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CD4+CD25+Foxp3+ regulatory T cells (Tregs), a vital component of the immune system, are responsible for maintaining immune homeostasis and preventing excessive immune responses. This review explores the signaling pathways of the cytokines that regulate Treg cells, including transforming growth factor beta (TGF-β), interleukin (IL)-2, IL-10, and IL-35, which foster the differentiation and enhance the immunosuppressive capabilities of Tregs. It also examines how, conversely, signals mediated by IL-6 and tumor necrosis factor -alpha (TNF-α) can undermine Treg suppressive functions or even drive their reprogramming into effector T cells. The B7 family comprises indispensable co-stimulators for T cell activation. Among its members, this review focuses on the capacity of CTLA-4 and PD-1 to regulate the differentiation, function, and survival of Tregs. As Tregs play an essential role in maintaining immune homeostasis, their dysfunction contributes to the pathogenesis of autoimmune diseases. This review delves into the potential of employing Treg-based immunotherapy for the treatment of autoimmune diseases, transplant rejection, and cancer. By shedding light on these topics, this article aims to enhance our understanding of the regulation of Tregs by cytokines and their therapeutic potential for various pathological conditions.

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Current understanding of CTLA-4: from mechanism to autoimmune diseases

Cited by 46 publications

References 185 publications

Immune and Microbial Signatures Associated with PD-1 Blockade Sensitivity in a Preclinical Model for HPV+ Oropharyngeal Cancer

Immune and Microbial Signatures Associated with PD-1 Blockade Sensitivity in a Preclinical Model for HPV+ Oropharyngeal Cancer

Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation?

Regulation of Treg cells by cytokine signaling and co-stimulatory molecules

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