Defect of regulatory T cells in patients with Omenn syndrome


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Type: Project Material

Department: Allergy and Clinical Immunology

No of Chapters: 5

Reference: Yes

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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
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 CD41 CD25high peripheral blood
T cells in 2 of these patients.
Results: We have observed that CD41CD25highT cells isolated
ex vivo from patients with OS failed to suppress proliferation of
autologous or allogenic CD41 responder T cells. Moreover,
despite individual variability in the fraction of circulating
FOXP31 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.


Omenn syndrome (OS) is a peculiar form of combined
immunodeficiency presenting with early-onset generalized eryth-
rodermia, failure to thrive, alopecia, lymphadenopathy, hepato-
splenomegaly, and intractable diarrhea.1 The immunologic
phenotype of OS is characterized by a normal to increased num-
ber of autologous T lymphocytes that express activation markers,
whereas circulating B cells are usually low or absent. Immuno-
globulin serum levels are very low, with the notable exception
of IgE levels, which are often increased.2,3
OS is most frequently associated with hypomorphic mutations
in the recombination-activating genes (RAGs), which impair but
do not complete abolish V(D)J recombination process, leading to
the generation only few productive antigen receptor gene rear-
rangements. As a consequence, T-cell repertoire is highly re-
stricted.4-7 More recently, additional gene defects that severely
reduce but do not completely ablate T-cell differentiation have
been shown to account for OS in a proportion of patients.8 What-
ever the molecular defects, oligoclonal and activated T cells in-
filtrate various organs, including skin, gut, spleen, and liver,
resulting in profound tissue damage.9-11 We have previously re-
ported that the thymus from patients with OS is markedly abnor-
mal, with lack of corticomedullary demarcation and absence of
Hassall bodies. In addition, the expression of autoimmune regu-
lator (AIRE) and AIRE-dependent tissue-restricted antigens is
severely reduced.12 On the basis of these findings, it has been hy-
pothesized that loss of central tolerance may contribute to the
immunopathology of OS. More recently, the lack of invariant
natural killer T cells (iNKT) has been proposed to contribute
to the immunopathology of OS.13 However, the possibility that
defects in other mechanisms of tolerance might be affected in
OS has not been tested so far. Peripheral dominant control of au-
toreactive T cells is primarily mediated by natural occurring
CD41CD251forkhead box protein P3 (FOXP3)1 regulatory T
(Treg) cells.14-17 Indeed, several human autoimmune diseases
have been associated with alterations in Treg-cell functions.18
The thymic development of this cell population is critically de-
pendent on the expression of the transcription repressor gene
19 which also represents a valuable marker to identify
both thymic and peripheral Treg cells.20 In human beings, there
is evidence that in the thymic medulla Treg cells are generated
from thymocytes on high-affinity T-cell receptor–peptide–
MHC—mediated interaction with a subset of activated dendritic
cells, driving these cells to acquire proper regulatory function.21
Although FOXP3 is a marker for human Treg cells, it cannot be considered specific for this population because it can also be
expressed, along with CD25, by activated CD41 cells.22-24
In the current study, we have analyzed 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 CD41 CD25high CD127low/– peripheral blood T
cells in 2 of these patients. Our results provide for the first time
evidence of impaired development and function of Treg cells in
OS, implying that both central and peripheral tolerance are com-
promised in this disease.


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