Defect of regulatory T cells in patients with Omenn syndrome

Background

Omenn syndrome (OS) is an autosomal-recessive disorder characterized by severe immunodeficiency and T-cell–mediated autoimmunity. The disease is caused by hypomorphic mutations in recombination-activating genes that hamper the process of Variable (V) Diversity (D) Joining (J) recombination, leading to the generation of autoreactive T cells. We have previously shown that in OS the expression of autoimmune regulator, a key factor governing central tolerance, is markedly reduced.

Objective

Here, we have addressed the role of peripheral tolerance in the disease pathogenesis.

Methods

We have analyzed forkhead box protein P3 (FOXP3) expression in peripheral blood T cells of 4 patients with OS and in lymphoid organs of 8 patients with OS and have tested the suppressive activity of sorted CD4⁺ CD25^high peripheral blood T cells in 2 of these patients.

Results

We have observed that CD4⁺CD25^highT cells isolated ex vivo from patients with OS failed to suppress proliferation of autologous or allogenic CD4⁺ responder T cells. Moreover, despite individual variability in the fraction of circulating FOXP3⁺ CD4 cells in patients with OS, the immunohistochemical analysis of FOXP3 expression in lymph nodes and thymus of patients with OS demonstrated a severe reduction of this cell subset compared with control tissues.

Conclusion

Overall, these results suggest a defect of regulatory T cells in OS leading to a breakdown of peripheral tolerance, which may actively concur to the development of autoimmune manifestations in the disease.

Key words: Immunodeficiency, V(D)J recombination, Omenn syndrome, regulatory T cells, FOXP3, anergy and tolerance, thymus and the development of T lymphocytes

Abbreviations used: AIRE, Autoimmune regulator, FOXP3, Forkhead box protein P3, HD, Healthy donor, OS, Omenn syndrome, RAG, Recombination-activating gene, Treg, Regulatory T