Novel PI(3)K-p85α/p110δ-ITK-LAT-PLC-γ2 and Fyn-ADAP-Carma1-TAK1 Pathways Define Reverse Signaling via FasL.

The role of FasL in initiating death signals through Fas is well characterized. However, the reverse signaling pathway downstream of FasL in effector lymphocytes is poorly understood. Here, we identify that FasL functions as an independent activation receptor in NK cells.

Tetramer-aided sorting and single-cell RNA sequencing facilitate transcriptional profiling of antigen-specific CD8+ T cells.

Background: Recent advances in single-cell technologies and an improved understanding of tumor antigens have empowered researchers to investigate tumor antigen-specific CD8+ T cells at the single-cell level. Peptide-MHC I tetramers are often utilized to enrich antigen-specific CD8+ T cells, which however, introduces the undesired risk of altering their clonal distribution or their transcriptional state. This study addresses the feasibility of utilizing tetramers to enrich antigen-specific CD8+ T cells for single-cell analysis.

MICA immune complex formed with alpha 3 domain-specific antibody activates human NK cells in a Fc-dependent manner.

Background: One of the mechanisms by which tumors evade immune surveillance is through shedding of the major histocompatibility complex (MHC) class I chain-related protein A and B (MICA/B) from their cell surface. MICA/B are ligands for the activating receptor NKG2D on NK and CD8 T cells. This shedding reduces cell surface levels of MICA/B and impairs NKG2D recognition.

Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell-Mediated Inflammation and Immunosuppression.

Immune-checkpoint protein V-domain immunoglobulin suppressor of T-cell activation (VISTA) controls antitumor immunity and is a valuable target for cancer immunotherapy. This study identified a role of VISTA in regulating Toll-like receptor (TLR) signaling in myeloid cells and controlling myeloid cell-mediated inflammation and immunosuppression. VISTA modulated the polyubiquitination and protein expression of TRAF6.

IL-27 promotes NK cell effector functions via Maf-Nrf2 pathway during influenza infection.

Influenza virus targets epithelial cells in the upper respiratory tract. Natural Killer (NK) cell-mediated early innate defense responses to influenza infection include the killing of infected epithelial cells and generation of anti-viral cytokines including interferon gamma (IFN-γ). To date, it is unclear how the underlying cytokine milieu during infection regulates NK cell effector functions.

Signaling in Effector Lymphocytes: Insights toward Safer Immunotherapy.

Receptors on T and NK cells systematically propagate highly complex signaling cascades that direct immune effector functions, leading to protective immunity. While extensive studies have delineated hundreds of signaling events that take place upon receptor engagement, the precise molecular mechanism that differentially regulates the induction or repression of a unique effector function is yet to be fully defined. Such knowledge can potentiate the tailoring of signal transductions and transform cancer immunotherapies.

IQGAP1: insights into the function of a molecular puppeteer.

The intracellular spatiotemporal organization of signaling events is critical for normal cellular function. In response to environmental stimuli, cells utilize highly organized signaling pathways that are subject to multiple layers of regulation. However, the molecular mechanisms that coordinate these complex processes remain an enigma.

Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner.

Sal-like protein 4 (SALL4) is a transcription factor that exists in two splice isoforms, SALL4a and SALL4b, and regulates transcription in embryonic stem cells, hematopoiesis, and acute myeloid leukemia. Constitutive overexpression of SALL4 in mice induces acute myeloid leukemia. Interestingly, a potential benefit of using SALL4 to facilitate ex vivo hematopoietic stem cell expansion has been proposed.

Signaling by Fyn-ADAP via the Carma1-Bcl-10-MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells.

Inflammation is a critical component of the immune response. However, acute or chronic inflammation can be highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma and various autoimmune disorders.

IL-22: An Evolutionary Missing-Link Authenticating the Role of the Immune System in Tissue Regeneration.

Tissue regeneration is a critical component of organ maintenance. The ability of lymphocytes to kill pathogen-infected cells has been well-studied. However, the necessity for lymphocytes to participate in reconstruction of destroyed tissues has not been explored until recently.

Clinical relevance of natural killer cells following hematopoietic stem cell transplantation.

Natural killer (NK) cells are one of the first cells to recover following allogeneic hematopoietic stem cell transplantation (HSCT), and are believed to play an important role in facilitating engraftment or preventing post-transplant infection and tumor recurrence. Recent studies have provided novel insights into the mechanisms by which NK cells mediate these highly clinically relevant immunological functions. In particular, the ability of NK cells to reduce the risk of graft versus host disease (GVHD) and increase the graft versus leukemia effect (GVL) in the setting of human leukocyte antigen (HLA)-haploidentical HSCT highlights their clinical potentials.

IQGAP1: a regulator of intracellular spacetime relativity.

Activating and inhibiting receptors of lymphocytes collect valuable information about their mikròs kósmos. This information is essential to initiate or to turn off complex signaling pathways. Irrespective of these advances, our knowledge on how these intracellular activation cascades are coordinated in a spatiotemporal manner is far from complete.

Transforming growth factor-beta-activated kinase 1 regulates natural killer cell-mediated cytotoxicity and cytokine production.

Carma1, a caspase recruitment domain-containing membrane-associated guanylate kinase, initiates a unique signaling cascade via Bcl10 and Malt1 in NK cells. Carma1 deficiency results in reduced phosphorylation of JNK1/2 and activation of NF-κB that lead to impaired NK cell-mediated cytotoxicity and cytokine production. However, the precise identities of the downstream signaling molecules that link Carma1 to these effector functions were not defined.

Functional dichotomy between NKG2D and CD28-mediated co-stimulation in human CD8+ T cells.

Both CD28 and NKG2D can function as co-stimulatory receptors in human CD8+ T cells. However, their independent functional contributions in distinct CD8+ T cell subsets are not well understood. In this study, CD8+ T cells in human peripheral blood- and lung-derived lymphocytes were analyzed for CD28 and NKG2D expression and function.

Rap1b facilitates NK cell functions via IQGAP1-mediated signalosomes.

Rap1 GTPases control immune synapse formation and signaling in lymphocytes. However, the precise molecular mechanism by which Rap1 regulates natural killer (NK) cell activation is not known. Using Rap1a or Rap1b knockout mice, we identify Rap1b as the major isoform in NK cells.