Phosphoinositide 3-kinase δ is a regulatory T-cell target in cancer immunotherapy

Tumour infiltration by regulatory T (Treg) cells contributes to suppression of the anti-tumour immune response, which limits the efficacy of immune-mediated cancer therapies. The phosphoinositide 3-kinase (PI3K) pathway has key roles in mediating the function of many immune cell subsets, including Treg cells. Treg function is context-dependent and depends on input from different cell surface receptors, many of which can activate the PI3K pathway. In this review, we explore how PI3Kδ contributes to signalling through several major immune cell receptors, including the T-cell receptor and co-stimulatory receptors such as CD28 and ICOS, but is antagonized by the immune checkpoint receptors CTLA-4 and PD-1. Understanding how PI3Kδ inhibition affects Treg signalling events will help to inform how best to use PI3Kδ inhibitors in clinical cancer treatment.     

Proliferative properties of murine intestinal intraepithelial lymphocytes (IEL): IEL expressing TCR alpha beta or TCR tau delta are largely unresponsive to proliferative signals mediated via conventional stimulation of the CD3-TCR complex.

Murine intestinal intraepithelial lymphocytes (IEL) were studied for their capacity to proliferate in vitro following stimulation of the T cell receptor (TCR)-associated CD3 epsilon molecule, or upon direct stimulation of the TCR complex itself. Although IEL consisted primarily of CD3+ T cells which included activated cytotoxic T lymphocytes as demonstrated in CD3- and TCR-mediated redirected cytotoxic assays, IEL displayed minimal proliferative responses following stimulation with anti-CD3, anti-TCR alpha beta, or anti-TCR tau delta monoclonal antibodies under soluble conditions, or under conditions which effect membrane cross-linking, including the addition of accessory cells to IEL cultures. The lack of proliferation induction could not be overcome by stimulation of IEL in the presence of T cell-dependent cytokines, phorbol ester, or interleukin-4. Moreover, unlike splenic T cells, stimulation of IEL failed to result in expression of interleukin-2 receptor, further demonstrating an inability of IEL to respond to exogenous proliferative signals. This study is the first to examine the proliferative potential of murine IEL following direct CD3 or TCR stimulation. The findings described here: (i) identify an important functional distinction between intestinal IEL and other peripheral alpha beta or tau delta T cells which generally respond well to proliferative signals mediated through the CD3-TCR complex, and (ii) demonstrate that on murine IEL the CD3-TCR complex can discriminate signals of lytic activity from those of cell proliferation.     

TCR-mediated hyper-responsiveness of autoimmune Galphai2(-/-) mice is an intrinsic naïve CD4(+) T cell disorder selective for the Galphai2 subunit

Heterotrimeric Gi signaling regulates immune homeostasis, sinceautoimmunity occurs upon disruption of this pathway. However,the role of the lymphocyte-expressed Gi subunits (Gi2 and 3)on T cell activation and cytokine production is poorly understood.To examine this role, we studied T lymphocytes from mice deficientin the Gi2 or Gi3 subunits. Gi2^-/- but not Gi3^-/- splenocyteswere hyper-responsive for IFN- and IL-4 production followingactivation through the TCR. Gi2^-/- T cells had a relaxed costimulatoryrequirement for IL-2 secretion and proliferation compared towild-type cells. Purified naïve Gi2^-/- T cells producedmore IL-2 than naïve wild-type T cells following TCR activation,indicating that the hyper-responsive cytokine profile was notdue to the expanded Gi2^-/- memory T cells, but involved an intrinsicT cell alteration. Cytokine hyper-responsiveness was not seenwhen purified Gi2^-/- T cells were stimulated with phorbol myristicacetate/ionomycin, localizing the alteration to a proximal TCR-specificsignaling pathway. Gi2^-/- CD4⁺ T cells were distinguished fromwild-type or Gi3^-/- T cells by a globally augmented TCR-inducedcalcium response. These findings indicate that Gi2^-/- mice havean intrinsic CD4⁺ T cell abnormality in TCR signaling whichmay be one cause of augmented T cell effector function and Gi2^-/-autoimmune susceptibility.     

The power and the promise of restimulation-induced cell death in human immune diseases

Summary: Controlled expansion and contraction of lymphocytes both during and after an adaptive immune response are imperative to sustain a healthy immune system. Both extrinsic and intrinsic pathways of lymphocyte apoptosis are programmed to eliminate cells at the proper time to ensure immune homeostasis. Genetic disorders of apoptosis described in mice and humans have established Fas and Bim as critical pro-apoptotic molecules responsible for T-cell death in response to T-cell receptor restimulation and cytokine withdrawal, respectively. Emerging evidence prompts revision of this classic paradigm, especially for our understanding of restimulation-induced cell death (RICD) and its physiological purpose. Recent work indicates that RICD employs both Fas and Bim for T-cell deletion, dispelling the notion that these molecules are assigned to mutually exclusive apoptotic pathways. Furthermore, new mouse model data combined with our discovery of defective RICD in X-linked lymphoproliferative disease (XLP) patient T cells suggest that RICD is essential for precluding excess T-cell accumulation and associated immunopathology during the course of certain infections. Here, we review how these advances offer a refreshing new perspective on the phenomenon of T-cell apoptosis induced through antigen restimulation, including its relevance to immune homeostasis and potential for therapeutic interventions.     

A signal transduction through a unique rat T cell specific antigen, 8H3.

A signal transduction was detected in various rat T cells by cross-linking of 8H3 antigen by 8H3 antibody. A rat T cell proliferative response induced by 8H3 antibody is dependent on the presence of adherent cells. When spleen cells were cultured in the presence of 8H3 antibody, only CD4-positive T cell proliferation was induced. These proliferative CD4-positive T cells express rat interleukin 2 receptor, alpha chain. Cross-linking of 8H3 antigen resulted in an increase in cytoplasmic free Ca2+ in T cells and phosphorylation of a 120 kDa component of the 8H3 antigen. It should be noted that cross-linking of 8H3 antigen together with CD4 antigen but not with CD8 antigen by suboptimal doses of 8H3 and corresponding antibodies initiated the mobilization of [Ca2+]i. Furthermore, physical association of 8H3 antigen with TCR was demonstrated by comodulation of these two molecular complexes in some T cells. Thus, 8H3 antigen is involved in rat T cell transmembrane signal transduction.     

Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma

Pancreatic adenocarcinoma is one of the deadliest cancers with poor survival and limited treatment options. Immunotherapy is an attractive option for this cancer that needs to be further developed. Tumours have evolved a variety of mechanisms to suppress host immune responses. Understanding these responses is central in developing immunotherapy protocols. The aim of this study was to investigate potential immune suppressor mechanisms that might occur during development of pancreatic tumours. Myeloid-derived suppressor cells (MDSC) from mice with spontaneous pancreatic tumours, mice with premalignant lesions as well as wild-type mice were analysed. An increase in the frequency of MDSC early in tumour development was detected in lymph nodes, blood and pancreas of mice with premalignant lesions and increased further upon tumour progression. The MDSC from mice with pancreatic tumours have arginase activity and suppress T-cell responses, which represent the hallmark functions of these cells. Our study suggests that immune suppressor mechanisms generated by tumours exist as early as premalignant lesions and increase with tumour progression. These results highlight the importance of blocking these suppressor mechanisms early in the disease in developing immunotherapy protocols.     

Expression profile and clonality of T-cell receptor beta variable genes in normal human endometrium

PROBLEM: In spite of their key immunological role, alphabeta+ T cells residing in endometrium have not been extensively explored. We analyzed here expression profile of TCRBV genes in normal human endometrium compared with peripheral blood. METHODS: Samples were taken from normal reproductive women. RT-PCR using BV-gene specific primers was performed on blood and endometrial samples. After blotting, hybridization with radiolabelled probe and autoradiography, relative expression of each TCRBV family was determined. Clonal expansions of the over-expressed genes were assessed by CDR3 length polymorphism. RESULTS: Only one gene (TCRBV7) was expressed significantly and two other genes marginally more in the endometrium compared with blood. All three TCRBV genes examined showed a rather restricted pattern in the endometrium in contrast to polyclonal patterns in the blood. CONCLUSION: Our results stress the similarities between T cells residing in different mucosal tissues and provide a basis for future investigations about endometrial T cells and their antigen specificities in gynecological problems.