A hallmark of mammalian immunity is the heterogeneity of cell fate that exists among pathogen-experienced lymphocytes. We show that a dividing T lymphocyte initially responding to a microbe exhibits unequal partitioning of proteins that mediate signaling, cell fate specification, and asymmetric cell division. Asymmetric segregation of determinants appears to be coordinated by prolonged interaction between the T cell and its antigen-presenting cell before division. Additionally, the first two daughter T cells displayed phenotypic and functional indicators of being differentially fated toward effector and memory lineages. These results suggest a mechanism by which a single lymphocyte can apportion diverse cell fates necessary for adaptive immunity.

The common gamma chain (gamma c) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors is defective in humans with XSCID. Mice lacking gamma c expression had hypoplastic thymuses; the thymocytes responded to gamma c-independent mitogens, but not gamma c-dependent stimuli. Splenic T cells were diminished at 3 weeks of age, but CD4+ T cells markedly increased by 4 weeks. B cells were greatly diminished in contrast with the situation in XSCID. NK cells, gamma delta intestinal intraepithelial lymphocytes, dendritic epidermal T cells, peripheral lymph nodes, and gut-associated lymphoid tissue were absent. These findings underscore the importance of gamma c in lymphoid development. Moreover, differences in humans and mice lacking gamma c expression indicate species-specific differences in the roles of gamma c-dependent cytokines or in the existence of redundant pathways. These mice provide an important model for studying the pathophysiology provide an important model for studying the pathophysiology of and gene therapy for human XSCID.

Interleukin-2 (IL-2) signaling requires the dimerization of the IL-2 receptor beta.(IL-2R beta) and common gamma (gamma c) chains. Mutations of gamma c can result in X-linked severe combined immunodeficiency (XSCID). IL-2, IL-4, IL-7 (whose receptors are known to contain gamma c), and IL-9 (whose receptor is shown here to contain gamma c) induced the tyrosine phosphorylation and activation of the Janus family tyrosine kinases Jak1 and Jak3. Jak1 and Jak3 associated with IL-2R beta and gamma c, respectively; IL-2 induced Jak3-IL-2R beta and increased Jak3-gamma c associations. Truncations of gamma c, and a gamma c, point mutation causing moderate X-linked combined immunodeficiency (XCID), decreased gamma c-Jak3 association. Thus, gamma c mutations in at least some XSCID and XCID patients prevent normal Jak3 activation, suggesting that mutations of Jak3 may result in an XSCID-like phenotype.

Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor gamma chain (gamma c) gene that encodes a shared, essential component of the receptors of interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. The Janus family tyrosine kinase Jak3 is the only signaling molecule known to be associated with gamma c, so it was hypothesized that defects in Jak3 might cause an XSCID-like phenotype. A girl with immunological features indistinguishable from those of XSCID was therefore selected for analysis. An Epstein-Barr virus (EBV)-transformed cell line derived from her lymphocytes had normal gamma c expression but lacked Jak3 protein and had greatly diminished Jak3 messenger RNA. Sequencing revealed a different mutation on each allele: a single nucleotide insertion resulting in a frame shift and premature termination in the Jak3 JH4 domain and a nonsense mutation in the Jak3 JH2 domain. The lack of Jak3 expression correlated with impaired B cell signaling, as demonstrated by the inability of IL-4 to activate Stat6 in the EBV-transformed cell line from the patient. These observations indicate that the functions of gamma c are dependent on Jak3 and that Jak3 is essential for lymphoid development and signaling.

The interleukin-2 (IL-2) receptor gamma chain (IL-2R gamma) is an essential component of high- and intermediate-affinity IL-2 receptors. IL-2R gamma was demonstrated to be a component of the IL-4 receptor on the basis of chemical cross-linking data, the ability of IL-2R gamma to augment IL-4 binding affinity, and the requirement for IL-2R gamma in IL-4-mediated phosphorylation of insulin receptor substrate-1. The observation that IL-2R gamma is a functional component of the IL-4 receptor, together with the finding that IL-2R gamma associates with the IL-7 receptor, begins to elucidate why deficiency of this common gamma chain (gamma c) has a profound effect on lymphoid function and development, as seen in X-linked severe combined immunodeficiency.

The interleukin-2 receptor gamma chain (IL-2R gamma) is a necessary component of functional IL-2 receptors. IL-2R gamma mutations result in X-linked severe combined immunodeficiency (XSCID) in humans, a disease characterized by the presence of few or no T cells. In contrast, SCID patients with IL-2 deficiency and IL-2-deficient mice have normal numbers of T cells, suggesting that IL-2R gamma is part of more than one cytokine receptor. By using chemical cross-linking, IL-2R gamma was shown to be physically associated with the IL-7 receptor. The presence of IL-2R gamma augmented both IL-7 binding affinity and the efficiency of internalization of IL-7. These findings may help explain the defects of XSCID. Given its role in more than one cytokine receptor system, the common gamma chain (gamma c) is proposed as the designation for IL-2R gamma.

T cell shape is dictated by the selective recruitment of molecules to different regions of the cell (polarity) and is integral to every aspect of T cell function, from migration to cytotoxicity. This study describes a mechanism for the regulation of T cell polarity. We show that T cells contain a network of asymmetrically distributed proteins with the capacity to dictate the subcellular localization of both cell surface receptors and morphological determinants in T cells. Proteins from the Scribble, Crumbs3, and Par3 complexes, previously shown to regulate epithelial polarity, were polarized in T cells containing either uropods or immunological synapses. Reduction in Scribble expression prevented the polarization of cell surface receptors and prevented morphological changes associated with uropod formation, migration, and antigen presentation. By dynamically coordinating molecular distribution throughout the T cell, this network provides a mechanism by which T cell function and polarity are linked.

Many autoimmune diseases exhibit familial aggregation, indicating that they have genetic determinants. Single nucleotide polymorphisms in PTPN2, which encodes T cell protein tyrosine phosphatase (TCPTP), have been linked with the development of several autoimmune diseases, including type 1 diabetes and Crohn's disease. In this study, we have identified TCPTP as a key negative regulator of TCR signaling, which might explain the association of PTPN2 SNPs with autoimmune disease. We found that TCPTP dephosphorylates and inactivates Src family kinases to regulate T cell responses. Using T cell-specific TCPTP-deficient mice, we established that TCPTP attenuates T cell activation and proliferation in vitro and blunts antigen-induced responses in vivo. TCPTP deficiency lowered the in vivo threshold for TCR-dependent CD8 + T cell proliferation. Consistent with this, T cell-specific TCPTP-deficient mice developed widespread inflammation and autoimmunity that was transferable to wild-type recipient mice by CD8 + T cells alone. This autoimmunity was associated with increased serum levels of proinflammatory cytokines and anti-nuclear antibodies, T cell infiltrates in non-lymphoid tissues, and liver disease. These data indicate that TCPTP is a critical negative regulator of TCR signaling that sets the threshold for TCR-induced naive T cell responses to prevent autoimmune and inflammatory disorders arising.