Ctla4, also known as cytotoxic T-lymphocyte antigen-4 or CD152, is a member of the immunoglobulin superfamily and an essential negative regulator of immune responses [4,8]. It is constitutively expressed on CD4+ CD25+ T regulatory lymphocytes and transiently on activated CD4+ and CD8+ T lymphocytes [4]. Ctla4, along with CD28 and ICOS, belongs to a family of immunoglobulin-related receptors responsible for T-cell immune regulation [1]. CD28 promotes T-cell activities, while Ctla4 inhibits T-cell responses, and they share common ligands, B7.1 and B7.2 [2,3]. This inhibitory function of Ctla4 promotes long-lived anergy in immune cells and prevents autoimmunity, playing a crucial role in T-cell-mediated autoimmunity and susceptibility to autoimmune diseases [4].

In CTLA4-haploinsufficiency, a complex disease of immune dysregulation, abatacept, a CTLA4-Fc fusion protein, has been used to alleviate immune dysregulation in both adult and pediatric cases [5]. In urothelial cancer, CTLA4, an inhibitory checkpoint on activated T cells, is being studied as a therapeutic target in combination with anti-PD1 or anti-PDL1 therapies. The combination approach has shown encouraging antitumour effects when administered pre-operatively, potentially transforming immunologically cold tumours into hot tumours [6]. Association studies of CTLA4 polymorphisms, such as the A49G polymorphism, with diseases like systemic lupus erythematosus (SLE) have yielded inconsistent findings [4]. A meta-analysis found no significant association between the CTLA4 + 49A/G polymorphism and the risk of hepatocellular carcinoma [7]. A new family with a recurrent missense variant in CTLA4 showed autoimmune phenotypes and prominent neurological manifestations, expanding the phenotypic spectrum associated with CTLA4 alterations [8].

In conclusion, Ctla4 is a key negative regulator of T-cell immune responses, playing a vital role in preventing autoimmunity. Studies on CTLA4-haploinsufficiency and its role in cancer, as well as association studies of its polymorphisms with autoimmune diseases, have enhanced our understanding of its functions. Model-based research, though not specifically detailed in terms of KO/CKO mouse models in these references, would further clarify its role in specific biological processes and disease conditions.

References:

1. Rowshanravan, Behzad, Halliday, Neil, Sansom, David M. 2017. CTLA-4: a moving target in immunotherapy. In Blood, 131, 58-67. doi:10.1182/blood-2017-06-741033. https://pubmed.ncbi.nlm.nih.gov/29118008/

2. Hosseini, Arezoo, Gharibi, Tohid, Marofi, Faroogh, Babaloo, Zohreh, Baradaran, Behzad. 2020. CTLA-4: From mechanism to autoimmune therapy. In International immunopharmacology, 80, 106221. doi:10.1016/j.intimp.2020.106221. https://pubmed.ncbi.nlm.nih.gov/32007707/

3. Gough, Stephen C L, Walker, Lucy S K, Sansom, David M. . CTLA4 gene polymorphism and autoimmunity. In Immunological reviews, 204, 102-15. doi:. https://pubmed.ncbi.nlm.nih.gov/15790353/

4. Kailashiya, Vikas, Sharma, Hanjabam Barun, Kailashiya, Jyotsna. 2019. Role of CTLA4 A49G polymorphism in systemic lupus erythematosus and its geographical distribution. In Journal of clinical pathology, 72, 659-662. doi:10.1136/jclinpath-2019-206013. https://pubmed.ncbi.nlm.nih.gov/31340988/

5. Lanz, Anna-Lisa, Riester, Martin, Peters, Philipp, Albert, Michael H, Hauck, Fabian. 2021. Abatacept for treatment-refractory pediatric CTLA4-haploinsufficiency. In Clinical immunology (Orlando, Fla.), 229, 108779. doi:10.1016/j.clim.2021.108779. https://pubmed.ncbi.nlm.nih.gov/34116213/

6. Stockem, Chantal F, Galsky, Matthew D, van der Heijden, Michiel S. 2023. Turning up the heat: CTLA4 blockade in urothelial cancer. In Nature reviews. Urology, 21, 22-34. doi:10.1038/s41585-023-00801-7. https://pubmed.ncbi.nlm.nih.gov/37608154/

7. Tan, Xiujuan, Liu, Chunfeng, Sun, Lingling. 2023. Association between CTLA4 + 49A/G polymorphism and risk of hepatocellular carcinoma: a systematic review and meta-analysis. In Nucleosides, nucleotides & nucleic acids, 43, 302-315. doi:10.1080/15257770.2023.2255626. https://pubmed.ncbi.nlm.nih.gov/37679967/

8. Genio, Edoardo, Lecca, Mauro, Ciccocioppo, Rachele, Errichiello, Edoardo. 2025. CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review. In Genes, 16, . doi:10.3390/genes16030306. https://pubmed.ncbi.nlm.nih.gov/40149457/