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The destruction of tumor cells by the immune system is under the control of positive and negative receptors that tightly regulate T-cell effector functions. The T-cell receptor (TCR) inhibitory molecule CD5 critically contributes to the regulation of antitumor immune responses. Indeed, the modulation of CD5 within the tumor microenvironment corresponds to a strategy adopted by tumor-specific cytotoxic T lymphocytes (CTLs) to optimize their cytotoxic and cytokine secretion functions. In this review, we provide insights into the immunobiology of CD5 and its role in regulating antitumor CD8 T-cell responses, and suggest the possibility of targeting CD5 to improve the efficacy of current immunotherapeutic approaches against cancer. [ABSTRACT FROM AUTHOR]

Mycolactone is a macrolide produced by Mycobacterium ulcerans with immunomodulatory properties. Here, we describe that in mouse, mycolactone injection led to a massive T-cell depletion in peripheral lymph nodes (PLNs) that was associated with defective expression of L-selectin (CD62-L). Importantly, preexposure to mycolactone impaired the capacity of T cells to reach PLNs after adoptive transfer, respond to chemotactic signals, and expand upon antigenic stimulation in vivo. We found that mycolactone-induced suppression of CD62-L expression by human primary T cells was induced rapidly at both the mRNA and protein levels and correlated with the reduced expression of one miRNA: let-7b. Notably, silencing of let-7b was sufficient to inhibit CD62-L gene expression. Conversely, its overexpression tended to up-regulate CD62-L and counteract the effects of mycolactone. Our results identify T-cell homing as a biological process targeted by mycolactone. Moreover, they reveal a mechanism of control of CD62-L expression involving the miRNA let-7b. [ABSTRACT FROM AUTHOR]

The phosphoinositide 3-kinase (PI3K) family of lipid kinases regulates diverse aspects of lymphocyte behavior. This review discusses how genetic and pharmacological tools have yielded an increasingly detailed understanding of how PI3K enzymes function at different stages of lymphocyte development and activation. Following antigen receptor engagement, activated PI3K generates 3-phosphorylated inositol lipid products that serve as membrane targeting signals for numerous proteins involved in the assembly of multiprotein complexes, termed signalosomes, and immune synapse formation. In B cells, class IA PI3K is the dominant subgroup whose loss causes profound defects in development and antigen responsiveness. In T cells, both class IA and IB PI3K contribute to development and immune function. PI3K also regulates both chemokine responsiveness and antigen-driven changes in lymphocyte trafficking. PI3K modulates the function not only of effector T cells, but also regulatory T cells; these disparate functions culminate in unexpected autoimmune phenotypes in mice with PI3K-deficient T cells. Thus, PI3K signaling is not a simple switch to promote cellular activation, but rather an intricate web of interactions that must be properly balanced to ensure appropriate cellular responses and maintain immune homeostasis. Defining these complexities remains a challenge for pharmaceutical development of PI3K inhibitors to combat inflammation and autoimmunity. [ABSTRACT FROM AUTHOR]

To investigate tumor resistance to T cell lysis, a resistant variant was selected after specific cytolytic T lymphocytes (CTL) selection pressure. Although the resistant variant triggered perform and granzyme B transcription in specific CTLs, as well as their degranulation, it exhibited a dramatic resistance to cytotoxic T cell killing. It also displayed strong morphological changes with alterations of the actin cytoskeleton. Electron microscopy analysis revealed a loosen interaction between CTL5 and the resistant variant despite the formation of apparently normal conjugates. Transcriptional profiling identified a gene expression signature that distinguished sensitive from resistant tumor targets. More notably, we found that actin-related genes ephrin-A1 and scinderin were overexpressed in resistant target. Silencing of these genes using RNA interference resulted in a restoration of normal cell morphology and a significant attenuation of variant resistance to CTL killing. Our present study shows that a shift in cytoskeletal organization can be used, by tumor cells, as a strategy to promote their resistance after CTL selection pressure. [ABSTRACT FROM AUTHOR]

During activation, T cells associate with antigen-presenting cells, a dynamic process that involves the formation of a broad area of intimate membrane contact known as the immunological synapse. The molecular intermediates that link initial antigen recognition to the cytoskeletal changes involved in this phenomenon have not yet been defined. Here we demonstrate that ezrin-radixin-moesin proteins are rapidly inactivated after antigen recognition through a Vav1-Rac1 pathway. The resulting disanchoring of the cortical actin cytoskeleton from the plasma membrane decreased cellular rigidity, leading to more efficient T cell-antigen-presenting cell conjugate formation. These findings identify an antigen-dependent molecular pathway that favors immunological synapse formation and the subsequent development of an effective immune response. [ABSTRACT FROM AUTHOR]

Activation of phosphoinositide 3-kinase (PI3K) at the immunological synapse between aT cell and an antigen-presenting cell (APC) has not been demonstrated. Using fluorescent-specific probes, we show here that the formation of an immunological synapse led to sustained production of 3'phosphoinositides in the T cell, whereby phosphatidylinositol-3,4,5-trisphosphate (PIP[sub 3]) but not phosphatidylinositol-3,4-bisphosphate was localized to the cell membrane. The accumulation of PIP[sub 3] after T cell activation preceded the increase in intracellular calcium. Neither the formation of conjugates between T cells and APCs nor signaling events such as phosphotyrosine accumulation and calcium increase changed substantially when PI3K was inhibited, and only a limited reduction in synthesis of interleukin 2 occurred. In T cell-APC conjugates, PIP[sub 3] accumulated at the T cell-APC synapse as well as in the rest of the T cell plasma membrane, which indicated unusual regulation of PI3K activity during antigen presentation. [ABSTRACT FROM AUTHOR]

The interaction of integrin αE(CD103)β7, often expressed on tumor-infiltrating T lymphocytes, with its cognate ligand, the epithelial cell marker E-cadherin on tumor cells, plays a major role in antitumor CTL responses. CD103 is induced on CD8 T cells upon TCR engagement and exposure to TGF-β1, abundant within the tumor microenvironment. However, the transcriptional mechanisms underlying the cooperative role of these two signaling pathways in inducing CD103 expression in CD8 T lymphocytes remain unknown. Using a human CTL system model based on a CD8+/CD103- T cell clone specific of a lung tumor-associated Ag, we demonstrated that the transcription factors Smad2/3 and NFAT-1 are two critical regulators of this process. We also identified promoter and enhancer elements of the human ITGAE gene, encoding CD103, involved in its induction by these transcriptional regulators. Overall, our results explain how TGF-β1 can participate in CD103 expression on locally TCRengaged Ag-specific CD8 T cells, thus contributing to antitumor CTL responses and cancer cell destruction. [ABSTRACT FROM AUTHOR]

Forkhead box O (FOXO) transcription factors favor both T cell quiescence and trafficking through their control of the expression of genes involved in cell cycle progression, adhesion, and homing. In this article, we report that the product of the fam6Sb gene is a new transcriptional target of FOXOl that regulates RhoA activity. We show that family with sequence similarity 65 member b (Fam65b) binds the small GTPase RhoA via a noncanonical domain and represses its activity by decreasing its GTP loading. As a consequence, Fam65b negatively regulates chemokine-induced responses, such as adhesion, morphological polarization, and migration. These results show the existence of a new functional link between FOXOl and RhoA pathways, through which the FOXOl target Fam65b tonically dampens chemokine-induced migration by repressing RhoA activity. [ABSTRACT FROM AUTHOR]

Summary: Helper T cells discriminate among different antigen-presenting cells to provide their help in a selective fashion. The molecular mechanisms leading to this exquisite selectivity are still elusive. Here, we demonstrate that immunological synapses are dynamic and adaptable structures allowing T cells to communicate with multiple cells. We show that T cells can form simultaneous immunological synapses with cells presenting different levels of antigenic ligands but eventually polarize toward the strongest stimulus. Remarkably, living T cells form discrete foci of signal transduction of different intensities during the interaction with different antigen-presenting cells and rapidly relocate TCR and Golgi apparatus toward the cell providing the strongest stimulus. Our results illustrate that, although T cell activation requires sustained signaling, T cells are capable of rapid synapse remodeling and swift polarization responses. The combination of sustained signaling with preferential and rapid polarization provides a mechanism for the high sensitivity and selectivity of T cell responses. [Copyright &y& Elsevier]