The role of programming in memory T-cell development

Recent studies suggest that memory T-cell differentiation continues for weeks or months following antigen clearance, although commitment to the memory lineage occurs during the effector stage of development. Several variables associated with priming, such as the duration of antigenic stimulation, degree of co-stimulation, cytokine environment, and CD4(+) T-cell help, may program epigenetic qualitative differences into the ensuing effector and memory populations. Defining what memory qualities best protect the organism from re-infection, as well as how commitment to the memory lineage is specified following T-cell activation remains an important goal.     

The role of growth hormone in T-cell development and reconstitution

Growth hormone (GH), directly or through GH-induction of insulin-like growth factor (IGF)-1, has been implicated in lymphocyte development and function. Recent studies have questioned the role of GH and IGF-1 in immune responses. This review examines experimental data describing the immunoregulatory function of GH and attempts to reconcile the literature.     

The role of T-cell receptor dimerization in T-cell activation

T-cell specificity is encoded in single T-cell receptors (TCRs) but monovalent interactions with peptide bound to the major histocompatibility complex (MHC) may not sufficiently account for the complexities associated with T-cell activation. This review proposes that TCRs undergo dimerization before activation and that this property might be essential for both T-cell antagonism and T-cell specificity, and may be pivotal for T-cell survival versus T-cell activation.     

The role of cyclin-dependent kinases in T-cell development, proliferation, and function

The transit of T lymphocytes through the cell cycle in response to extracellular signals is controlled in large part by the ordered expression and degradation of cyclins and cyclin-dependent kinases and their negative regulators, the cyclin-dependent kinase inhibitors. This review outlines findings that have provided insights into how T lymphocytes integrate signals from their antigen, costimulatory, and cytokine receptors to drive cell cycle progression and discusses how the coordinated activities of these families of proteins influence multiple aspects of T-cell function, from thymic development and peripheral homeostasis to antigen-driven responses and the induction of T-cell memory and tolerance.     

A role for a pre-T-cell receptor in T-cell development

Expression of a productive T-cell receptor (TCR) β gene has profound consequences for T-cell development, preceding an increase in thymocyte number, appearance of CD4 and CD8 coreceptors and suppression of further TCRβ-gene rearrangement. Here Marcus Groettrup and Harald von Boehmer discuss the data obtained in various experimental models and describe a novel signal transducing receptor complex on pre-T cells, which may regulate the TCRβ-induced developmental changes.     

The role of IL-27 in the development of T-cell responses during parasitic infections

Summary: The recognition that CD4⁺ T‐cell responses could be divided into at least two functional subsets either dominated by production of interferon (IFN)‐γ and associated with cell‐mediated immunity (Th1) or characterized by production of interleukin (IL)‐4 and IL‐5 and associated with humoral immunity (Th2) provided a basis to understand the role of T cells in resistance or susceptibility to different types of pathogens. As a consequence, many studies have focused on the identification of cytokines that influence these events. For example, the development of Th1‐type responses is largely dependent on IL‐12. However, other cytokines also affect this process, and initial studies revealed that IL‐27, a cytokine with close structural and functional similarity to IL‐12, can promote Th1 responses required for immunity to Leishmania major. Subsequent work with IL‐27R (WSX‐1)‐deficient mice infected with Toxoplasma gondii or Trypanosoma cruzi revealed that the IL‐27/IL‐27R system can act as a negative regulator of inflammatory T‐cell responses. The aim of this review is to discuss recent studies from these laboratories on the role of IL‐27 in immunity to parasitic infections in the context of previous work and to highlight the pleiotropic effects of the IL‐27/IL‐27R system in the development and regulation of Th1 and Th2 responses.     

The role of ERK5 in T-cell signalling

The mitogen-activated protein kinase (MAPK) ERK5 plays an important role in mammary epithelial proliferation, endothelial cell survival and normal embryonic development. In nonhaematopoietic cells, mitogenic and stress signals activate the ERK5 cascade. Here, we investigated the role of the ERK5 pathway in T-cell activation and show that primary and leukaemic T cells express ERK5, whose activating phosphorylation is induced by antibodies against CD3 but not by phorbol myristate acetate treatment. ERK5 localized in the cytosol and nucleus in quiescent and activated T cells. In the latter, ERK5 phosphorylation was mainly observed in the nucleus. Selective activation of the ERK5 cascade by transfecting constitutively active MEK5 and wildtype ERK5 induced a reporter gene driven by the IL-2 promoter while barely affecting CD69 expression. These results suggest a new role for the ERK5 cascade in intracellular signalling in T cells.     

The possibility of B-cell-dependent T-cell development

The development of T cells is thought to be independent of B cells. However, defects in cell-mediated immunity in individuals with B-cell deficiency suggest the contrary. To test whether B cells affect T-lymphocyte development, we constructed mice with a monoclonal T-cell compartment (MT) and monoclonal B- and T-cell compartments (MBTs). In these mice, the T cells expressed a DO 11.10 transgenic (DO-T) cell receptor restricted to major histocompatibility complex (MHC) class IId. While CD4+ DO-T lymphocytes are rare in transgenic H-2b MT mice, we found that in H-2b MBT mice under the influence of B cells, DO-T lymphocytes mature into large numbers of CD4+ peripheral T cells. H-2b MBT mice have more CD4+ thymocytes than H-2b MT mice. These data are consistent with the view that B cells play some role in thymocyte development.     

The role of the PI3K-AKT kinase pathway in T-cell development beyond the beta checkpoint

The PI3K-AKT pathway can mediate diverse biological responses and is crucial for optimal immune responses and lymphocyte development. Deletion of PI3K subunits or AKT leads to blockage of T-cell development at the TCR-beta checkpoint. Studies with over-expression of constitutively activated AKT have implicated this pathway in anti-apoptosis of developing thymocytes and in development of regulatory T cells. However, the role of endogenous PI3K-AKT in T-cell development beyond the TCR-beta checkpoint remains unclear. Here, we inhibited the endogenous PI3K-AKT pathway in thymocytes after double negative stages by expressing the negative regulator, PTEN. These mice exhibit normal early T-cell development, but the transition from intermediate single positive to double positive (DP) thymocytes is inhibited, leading to a significantly decreased number of DP, single positive thymocytes and peripheral T cells. Proliferation of peripheral T cells is reduced but apoptosis of DP cells and subsequent T-cell maturation, including regulatory T cells, are normal. AKT phosphorylation can be readily observed in most WT T-cell compartments but not DP thymocytes in response to TCR activation. Thus, the PI3K-AKT pathway is crucial for the transition of intermediate single positive to DP thymocytes but is dispensable for apoptosis and maturation of developing thymocytes.     

The extrathymic T-cell development pathway.

In normal mice, not all T-lineage cells are generated and selected in the thymus; an alternative, extrathymic, development pathway exists. Extrathymic T cells are rare in the spleen and lymph nodes, but are abundant in some tissues, such as the gut. Here, Benedita Rocha, Pierre Vassalli and Delphine Guy-Grand discuss the rules of selection of extrathymic T cells, assess the possible role of these cells in the defence of epithelial integrity and their potential role in autoimmune disease.     

Cytokines in T-cell development

The thymus provides a unique environment for the development of T cells, supporting both precursor cell proliferation and differentiation. The control of these processes is unknown but they may be mediated by cytokines, or other soluble factors, or by interactions with specific elements of the thymic stroma. Here, Simon Carding, Adrian Hayday and Kim Bottomly describe cellular, immunochemical and molecular studies of the production and action of cytokines within the human and mouse thymus and demonstrate their essential role in T-cell development.     

The role of Grb2-associated proteins in T-cell activation

Recently, attention Ins focused on the role of adaptor proteins as modulators of signal transduction. Grb2, a cytosolic protein comprising two src-homology 3 (SH3) domains flanking a single SH2 domain, plays an important role in coupling receptor tyrosine kinases with downstream signals. In this article, proteins that associate with Grb2 in T cells are discussed, and models are presented suggesting how these interactions may be important far T-cell activation.     

The role of cytokines in T-cell memory in health and disease

Upon stimulation with their cognate antigen, naive T cells undergo proliferation and differentiation into effector cells, followed by apoptosis or survival as precursors of long-lived memory cells. These phases of a T-cell response and the ensuing maintenance of memory T cells are shaped by cytokines, most notably interleukin-2 (IL-2), IL-7, and IL-15 that share the common γ chain (γ_c) cytokine receptor. Steady-state production of IL-7 and IL-15 is necessary for background proliferation and homeostatic survival of CD4⁺ and CD8⁺ memory T cells. During immune responses, augmented levels of IL-2, IL-15, IL-21, IL-12, IL-18, and type-I interferons determine the memory potential of antigen-specific effector CD8⁺ cells, while increased IL-2 and IL-15 cause bystander proliferation of heterologous CD4⁺ and CD8⁺ memory T cells. Limiting availability of γ_c cytokines, reduction in regulatory T cells or IL-10, and persistence of inflammation or cognate antigen can result in memory T cells, which fail to become cytokine-dependent long-lived cells. Conversely, increased IL-7 and IL-15 can expand memory T cells, including pathogenic tissue-resident memory T cells, as seen in lymphopenia and certain chronic-inflammatory disorders and malignancies. These abovementioned factors impact immunotherapy and vaccines directed at memory T cells in cancer and chronic infection.     

The role of CD8+ T-cell response in HIV infection

CD8+ T-cells with cytotoxic (CTL) activity play a pivotal role in controlling viral infections. Although most patients chronically infected with HIV have CTL response against the virus, for reasons that are not well understood this response is not able to successfully control viral replication. The crucial role of this type of response has been clearly demonstrated in the setting of acute infection using the simian model of AIDS, in which a strong CTL response develops, supporting its role in humans. This approach has been possible due to the development of new assays to quantify CTL activity with great sensitivity and specificity. The interaction of CTL response and HIV during this acute stage of infection is crucial, since it most probably determines the viral set-point and thus the rate of HIV disease progression. In the setting of chronic HIV infection, the use of tetrameric complexes and IFN-gamma production assays have made it possible to investigate the different functional aspects of these cells and have also facilitated the evaluation of this response in large patient populations. Defects in cytokine production and in perforin expression have been found, as well as alterations in phenotypic maturation and a low proliferation of these cells. All these findings have been cited to explain the inability of CTLs to efficiently control virus replication. Nonetheless, accumulating evidence points toward an important role for CTL response in the partial containment of HIV replication in chronic infection. An especially strong support for this observation derives from studies analyzing the selective pressure exerted by the immune response over viral evolution. Very recently, longitudinal and cross-sectional studies in large populations of patients have demonstrated that viral evolution is in part driven by HIV-specific T-cell responses.