Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Despite the progress achieved in its treatment, 20% of cases relapse and no longer respond to chemotherapy. The most common phenotype of ALL cells share surface antigens with very early precursors of B cells and are therefore believed to originate from this lineage. Characterization of the growth requirement of ALL cells indicated that they were dependent on various cytokines, suggesting paracrine and/or autocrine growth regulation. Because many cytokines induce tyrosine phosphorylation in lymphoid progenitor cells, and constitutive tyrosine phosphorylation is commonly observed in B-lineage leukaemias, attempts have been made to develop protein tyrosine kinase (PTK) blockers of leukaemia cell growth. Here we show that leukaemic cells from patients in relapse have constitutively activated Jak-2 PTK. Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis.

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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.

he t-cell-receptor complex consists of the a and b or g and d variant chains, paired as mutually exclusive heterodimers in association with the invariant chains CD3 g , d , e , and z . T cells with a and b chains are referred to as a / b T cells, and those with g and d chains are called g / d T cells. During development, the CD3 protein complex plays an important part in the transition of thymocytes from CD4¡CD8¡ double-negative immature precursors to a CD4+CD8+ double-positive stage and finally to the mature CD4+CD8¡ or CD4¡CD8+ single-positive T cell. 1-5 Selective deficiency of CD3 component g , d , e , or z in mice, achieved by gene knockout, causes mild-to-severe, although incomplete, blockage of T-cell development. 6-10 Similarly, CD3 g or CD3 e deficiency in humans brings about a partial arrest of T-cell maturation and only moderate immunodeficiency. 11, 12 We report a novel defect in the CD3 d gene in three members of a kindred with a form of severe combined immunodeficiency (SCID) characterized by the absence of T cells but normal numbers of B cells (T¡B+ SCID). These three patients had an early arrest in T-cell development, with a nearly complete absence of circulating mature T cells and a complete lack of g / d T cells. Our results suggest that, unlike CD3 e and CD3 g , CD3 d is essential for T-cell development.We studied a kindred of Mennonite descent that shared multiple consanguineous links across several generations. Three patients with SCID were identified in this family. SCID was diagnosed in Patient 1 immediately after birth, after an examination performed because of previous cases in the family (Patients 2 and 3). She subsequently underwent bone marrow transplantation and is alive and well, with full immune reconstitution, three years later. Patient 2, a male cousin of Patient 1, was admitted at the age of two months because of fever, tachypnea, and tachycardia. Rapidly developing respiratory arrest required assisted ventilation, and he died of multiorgan failure. Adenovirus was identified in stool, urine, and bronchial secretions.Patient 3, a male cousin of Patients 1 and 2, was well and thriving until two and a half months of age, when chronic diarrhea developed. At three and a half months of age, the patient was admitted with respiratory distress, lethargy, and jaundice. On examination, he was noted to have hepatomegaly, and liver-function tests were markedly abnormal. He was transferred from another hospital with increased respiratory distress and died 12 hours later from rapidly developing refractory hypotension, liver failure, pulmonary hemorrhage, disseminated intravascular coagulopathy, and hemorrhagic shock. Cytomegalovirus was identified in multiple tissues obtained at autopsy.Flow-cytometric analyses of peripheral-blood lymphocytes from these patients showed a slight reduction in total lymphocyte counts in Patients 1 and 2 and a marked t case reportThe New England Journal of Medicine Downloaded from nejm.org at RUTGERS UNIV ALEXANDER LIBRARY on August 11, 2015. For personal use only....

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• IL21-mediated induction of CD25 expression on naïve human B cells requires STAT3.• A lack of response to IL-2 may amplify humoral immunodeficiency in patients with STAT3, IL2RG, or IL21R mutations due to unresponsiveness to IL21.

Eph receptor tyrosine kinases and their ligands, the ephrins, are known to play an important role in regulating cell migration and targeting in neuronal and endothelial cells. Recently, it hasbeen shown that lymphoid cells also express Eph receptors, raising the possibility that Eph receptors may similarly regulate lymphocyte migration. Chemotaxis in response to soluble chemokine factors is an essential facet of T cell biology. We demonstrate here that T cell chemotaxis in response to both the stromal cell‐derived factor (SDF)‐1α and macrophage inflammatory protein 3β chemokines is modulated by costimulation with ephrins. Both ephrin‐A and ephrin‐B ligands were found to modify the chemotactic responses of a T cell line and primary T cells. Ephrin‐A1, in particular, strongly inhibited chemotaxis. In accordance with the tyrosine kinase activity of EphA receptors, ephrin‐A1 stimulation induced rapid intracellular tyrosine phosphorylation in T cells. Although strongly inhibiting chemotaxis, ephrin‐A1 costimulus did not affect many of the signaling events downstream of the SDF‐1α receptor CXCR4, including calcium flux and activation of MAPK. Rather, ephrin‐A1 altered the balance of small G protein activity in T cells. Ephrin‐A1 stimulation prevented SDF‐1α–induced activation of cdc42, while simultaneously inducing rho activation. Ultimately, ephrin‐A1 was found to inhibit chemokine‐induced actin polymerization, thereby blocking migration. Ubiquitous ephrin expression in vivo creates enormous potential for T cells to encounter these ligands, suggesting that Eph receptors and ephrins may be important regulators of T cell migration.