Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor

Abstract

Profound cellular immunodeficiency occurs as the result of mutations in proteins involved in both the differentiation and function of mature lymphoid cells. We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor ␣ chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2. This immunodeficiency is characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development. Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inf lammation. Although mature T cells are present, the absence of CD25 does affect the differentiation of thymocytes. While displaying normal development of CD2, CD3, CD4, and CD8 expression, CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2.The high-affinity receptor for interleukin 2 (IL-2) (1) is composed of three subunits: ␣ (CD25), ␤ (CD122), and ␥ (␥ common ). While the ␤ and ␥ chains are constitutively expressed upon T lymphocytes, ␣ expression is restricted to the early stages of thymocyte development and to activated mature T lymphocytes. Although the ␤ and ␥ chains together can form an IL-2 receptor (IL-2R) of low affinity, the ␣ chain cannot form a functional receptor in the absence of the others (1). The presence of the high-affinity receptor upon activated peripheral T cells is believed to be necessary for optimal proliferative responses to IL-2 after stimulation of the T cell antigen receptor; however the role of the ␣␤␥ complex upon triplenegative thymocytes is less certain.Deletion of the IL-2R ␥ chain in humans results in the development of severe combined immunodeficiency (2) (Xlinked) characterized by a great reduction in, or absence of, peripheral T lymphocytes (3), due to the participation of the ␥ chain in multiple cytokine receptor complexes (i.e., with interleukins 2, 4, 7, 9, and 15). In mice, B cell development is also ablated (4). In sharp contrast, the absence of CD122 manifests in the constitutive activation of B and T lymphocytes accompanied by the development of autoimmune responses resulting in premature death (5). The absence of CD25 in mice would appear to cause the least severe impairment of the three. Young CD25-null mice have phenotypically normal T and B cell populations, while older animals exhibit enlarged lymphoid glands due to increased B and T cell populations (as the result of inefficient activation-induced cell death) and a propensity to develop autoimmune disorders (6).We describe here a human mutation of CD25 ablating its expression and the consequences upon immune function. Analysis of this patient suggests that expression of the IL-2R ␣ chain is necessary not only in the functional responses of mature T cells but also in preventing the generation and͞or controlling of autoreactive T lymphocytes. MATERIALS AND METHODSTissue Section Pr...

IL‐2Rβ links IL‐2R signaling with Foxp3 expression

“…Both il2 -/-and il2ra -/-animals are characterized by the accumulation of activated CD4 + T cells, production of autoantibodies, development of inflammatory bowel disease, and morbidity by approximately 16 wk of age [9,11,12,40]. It has been proposed that Foxp3 + cells are attracted to and expand in response to the developing inflammation characterizing il2ra -/-animals [41].…”

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

“…IL-2Ra only contributes to IL-2 binding a nity but not to the recruitment of signaling molecules. However, its importance in the development of a normal immune response is emphasized by the ®nding that a truncation mutant of IL-2Ra results in an immunode®-ciency in humans characterized by an increased susceptibility to viral, bacterial and fungal infections (Sharfe et al, 1997). In addition, gene targeting analysis also reveals that IL-2Ra-de®cient mice exhibit autoimmunity and premature death (Willerford et al, 1995).…”

Matched unrelated bone marrow transplant for T+ combined immunodeficiency

“…Levels of serum Abs to tetanus were measured by ELISA and polio Ab titers were determined by complement fixation. 8,9,[11][12][13][14][15]19 Quantification of TCR excision circles The amount of signal joint TCR excision circles adjusted to CD4 þ and CD8 þ T-cell subsets was determined by real-time quantitative PCR, as described previously. 21 The number of TCR excision circles in a given sample was compared to a value obtained with 10-fold serial dilutions of an internal standard provided by Dr Daniel Douek (Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA).…”

“…8,9,[11][12][13][14][15]19 For lymphocyte proliferation studies, cells were harvested after 3 days and samples counted in a liquid scintillation counter. All assays were performed in triplicate and stimulation index was calculated as the ratio between stimulated and nonstimulated lymphocyte responses and compared with stimulation index obtained from controls.…”

“…In recent years, patients with mutations in Jak-3, Zap-70, IL-2Ra and CD3 were reported to have autologous T cells and/or residual T-cell function, commonly referred to as T þ CID. [7][8][9][10] Moreover, even patients with X-linked SCID, such as those with the R222C mutation, may present as T þ CID. 11,12 Such patients present with near-normal or normal numbers of circulating T cells and responses to mitogens as well as having normal thymus morphology.…”