Background: MHC class II (MHC-II) molecules play a pivotal role in the development, activation, and homeostasis of CD4+ TH cells in the thymus. The absence of MHC-II molecules causes severe T-cell immunodeficiency. Objective: We sought to study thymic function, including T-cell receptor excision circle (TREC) quantification, in patients with MHC-II deficiency. Methods: Eight MHC-II-deficient patients underwent a thorough T-cell immunologic work-up, including thymic activity, which was estimated based on TREC levels and T-cell receptor (TCR) genes, as well as analysis of several sequential human TCR gene rearrangements. Results: In vitro responses to mitogens were normal or only slightly reduced, and flow cytometric evaluations of the TCR-Vβ repertoires of total CD3+ lymphocytes were normal in all patients. However, both the flow cytometric evaluation of the TCR-Vβ repertoire on CD4+ cells and spectratyping evaluation of the TCR-Vγ repertoire on total CD3+ lymphocytes showed clonal abnormalities. TRECs were present in all patients in both total lymphocytes and sorted CD4+ cells. Additionally, TRECs were detected in genomic DNA obtained from Guthrie cards with dried blood spots. Quantitative RT-PCR assessment of different TCR gene rearrangement events revealed lower levels in MHC-II-deficient patients compared with levels seen in healthy control subjects. This was irrespective of the total lymphocyte numbers, suggesting a reduced global thymic activity. Conclusions: Our report highlights potential pitfalls in diagnosing MHC-II deficiency and emphasizes the probable importance of MHC-II molecules in the normal thymic maturation process of T cells. Patients with MHC-II deficiency have detectable TRECs and might therefore be missed by a TREC-based newborn screening program.
- MHC class II
- T-cell receptor excision circle (TREC)
- T-cell receptor repertoire
- neonatal screening
- severe combined immunodeficiency