CD3 subunit deficiency (CD3SD) causes combined immunodeficiency (CID) and severe CID (SCID). To elucidate the clinical, laboratory, and genetic features of patients with different CD3SD subtypes. We evaluated the data of five patients with CD3ε (two), CD3γ (two), and CD3δ (one) deficiencies from our institution. In addition, we reviewed the medical literature for cases of CD3SD. We identified two novel homozygous CD3 variants. In addition, we identified 44 CD3SD cases in the literature. In total, we analyzed the results of 49 patients. Our review of the medical literature revealed 11, 12, 18, and three patients with CD3ε, CD3γ, CD3δ, and CD3ζ deficiency, respectively. Of the 49 patients, 40 had an SCID profile, whereas nine with CD3γ variants had a CID profile. The patients with SCID presented with typical symptoms, including recurrent infections (18 of 40; 45%), diarrhea (13 of 40; 33%), and candidiasis (12 of 40, 30%). Recurrent sinopulmonary infections (four of nine; 45%), thyroiditis (four of nine; 45%), and bronchiectasis (four of nine; 45%) were common in patients with CID. Almost 70% of patients with SCID (27 of 40) underwent hematopoietic stem cell transplantation. Our results show that patients with CD3δ, CD3ε, and CD3ζ deficiencies typically present with a classic SCID phenotype. In contrast, patients with CD3γ deficiency may either show an SCID phenotype or a milder, less severe CID phenotype. Importantly, autoimmunity may be the sole manifestation of CD3γ deficiency.

The T-cell receptor (TCR)/CD3 complex is crucial for T-cell development and regulation. In humans, CD3D, CD3E, and CD3Z gene defects cause severe combined T- and B-cell immunodeficiency. However, CD3G mutations alone lead to a less severe condition, which is mainly characterized by autoimmunity. In the present study, we report the case of a 36-year-old male who presented with recurrent sinopulmonary infections without opportunistic infections; this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation. This patient had the common variable immunodeficiency (CVID) phenotype and received regular immunoglobulin infusions over 20-years; he gradually developed nodular regenerative hyperplasia over a 5-year period. Distinct from the previously reported CD3G mutations, which mainly present as autoimmunity, the novel CD3G deletion (c.del213A) in our patient caused an obvious decrease in switched memory B cells and diminished CD40L expression. However, sufficient Treg suppression function was maintained so that he remained free of autoimmune thyroiditis (AIT), inflammatory bowel disease (IBD), and autoimmune pancytopenia. A PubMed search for this rare disease entity revealed seven Turkish and two Spanish patients (five unrelated families). Among a total of 20 alleles, there were 14 splicing mutations (80(-1)G>C), two missense mutations (c.1G>A), two nonsense mutations (c.250A>T), and two deletions (c.del213A). Three patients presented with isolated AIT without significant infections. Three patients died, one from a severe infection at 31 months, one from post-transplant respiratory failure due to viral pneumonia at 17 months, and one from graft-vs.-host disease at 47 months. Those experiencing opportunistic infections, severe life-threatening infections in need of hematopoietic stem cell transplantation, and IBD-like diarrhea had a significantly higher mortality rate compared with those without these features (p = 0.0124, p = 0.01, and p = 0.0124, respectively). The patients with AIT had a significantly better prognosis (p = 0.0124) to those without AIT. Our patient with the novel CD3G mutation presented with predominant B-cell deficiency overlapping with the CVID phenotype but without recognizable autoimmunity, which was consistent with his normal Treg suppression function.