Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 9 2 2026 06 29 238 238 Ayda Firouzabadi Student Research Committee, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran Sarehsadat Ebrahimi Division of Allergy and Clinical Immunology, Department of Pediatrics, Pediatrics Center of Excellence, Children’s Medical Center, Tehran, University of Medical Sciences, Tehran, Iran 2026 06 22 2026 06 29 Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) deficiency is a primary immune regulatory disorder caused by heterozygous germline loss-of-function variants in the CTLA4 gene. CTLA-4 is expressed mainly on activated T cells and regulatory T cells that plays a key role in maintaining immune tolerance by limiting T-cell activation. Also, CTLA-4 has recently become a key target in immune checkpoint-based therapeutics, particularly in cancer treatment via the use of monoclonal antibodies against this molecule. Loss of CTLA-4 function leads to uncontrolled T-cell activation and impaired Treg-mediated immune regulation. Consequently, this immune dysregulation underlies the coexistence of autoimmunity and immune deficiency. Hypogammaglobulinemia is one of the most common immunologic findings in CTLA-4 deficiency and may resemble common variable immunodeficiency. However, CTLA-4 deficiency is a multisystem disorder. Clinical manifestations are highly variable and may include recurrent respiratory infections, bronchiectasis, chronic diarrhea, malabsorption, autoimmune cytopenia, lymphadenopathy, splenomegaly, and organ infiltration. Laboratory findings commonly include lymphopenia, reduced naïve CD4⁺ T cells, increased activated T cells, impaired regulatory T-cell function, reduced CD19⁺ B cells, decreased class-switched memory B cells, expanded CD21-low B cells, reduced natural killer cells, and low serum immunoglobulin levels. Recognition of these clinical and laboratory features is essential for early diagnosis, appropriate management, and improved long-term outcomes in patients with CTLA-4 deficiency. This study reviews the pathophysiology, clinical manifestations and laboratory findings in patients with CTLA-4 deficiency. https://igj.tums.ac.ir/index.php/igj/article/view/238