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...

Protein tyrosine phosphatases act in conjunction with protein kinases to regulate the tyrosine phosphorylation events that control cell activation and differentiation. We have isolated a previously undescribed human phosphatase, Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain. The noncatalytic domain contains four proline-rich potential SH3 domain binding sites and an NXXY motif that, if phosphorylated, may be recognized by phosphotyrosine binding (PTB) domains. Comparison of the Lyp amino acid sequence with other known proteins shows 70% identity with the murine phosphatase PEP. The human Lyp gene was localized to chromosome 1p13 by fluorescence in situ hybridization analysis. We also identified an alternative spliced form of Lyp RNA, Lyp2. This isoform encodes a smaller 85-kD protein with an alternative C-terminus. The lyp phosphatases are predominantly expressed in lymphoid tissues and cells, with Lyp1 being highly expressed in thymocytes and both mature B and T cells. Increased Lyp1 expression can be induced by activation of resting peripheral T lymphocytes with phytohemagglutinin or anti-CD3. Lyp1 was found to be constitutively associated with the proto-oncogene c-Cbl in thymocytes and T cells. Overexpression of lyp1 reduces Cbl tyrosine phosphorylation, suggesting that it may be a substrate of the phosphatase. Thus, Lyp may play a role in regulating the function of Cbl and its associated protein kinases.