Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

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The blockade of immune checkpoints in cancer immunotherapy

For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

/pdf/the-nox-family-of-ros-generating-nadph-oxidases-physiology-zjc88zvh59.pdf

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

▪ Abstract T cells play a central role in the initiation and regulation of the immune response to antigen. Both the engagement of the TCR with MHC/Ag and a second signal are needed for the complete activation of the T cell. The CD28/B7 receptor/ligand system is one of the dominant costimulatory pathways. Interruption of this signaling pathway with CD28 antagonists not only results in the suppression of the immune response, but in some cases induces antigen-specific tolerance. However, the CD28/B7 system is increasingly complex due to the identification of multiple receptors and ligands with positive and negative signaling activities. This review summarizes the state of CD28/B7 immunobiology both in vitro and in vivo; summarizes the many experiments that have led to our current understanding of the participants in this complex receptor/ligand system; and illustrates the current models for CD28/B7-mediated T cell and B cell regulation. It is our hope and expectation that this review will provoke additional ...

Cd28/b7 system of t cell costimulation

The role of the cell-surface molecule CTLA-4 in the regulation of T cell activation has been controversial. Here, lymph nodes and spleens of CTLA-4-deficient mice accumulated T cell blasts with up-regulated activation markers. These blast cells also infiltrated liver, heart, lung, and pancreas tissue, and amounts of serum immunoglobulin were elevated. The mice invariably became moribund by 3 to 4 weeks of age. Although CTLA-4-deficient T cells proliferated spontaneously and strongly when stimulated through the T cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation. Thus, CTLA-4 acts as a negative regulator of T cell activation and is vital for the control of lymphocyte homeostasis.

https://science.sciencemag.org/content/sci/270/5238/985.full.pdf

Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4

Co-stimulatory and co-inhibitory receptors have a pivotal role in T cell biology, as they determine the functional outcome of T cell receptor (TCR) signalling. The classic definition of T cell co-stimulation continues to evolve through the identification of new co-stimulatory and co-inhibitory receptors, the biochemical characterization of their downstream signalling events and the delineation of their immunological functions. Notably, it has been recently appreciated that co-stimulatory and co-inhibitory receptors display great diversity in expression, structure and function, and that their functions are largely context dependent. Here, we focus on some of these emerging concepts and review the mechanisms through which T cell activation, differentiation and function is controlled by co-stimulatory and co-inhibitory receptors.

/pdf/molecular-mechanisms-of-t-cell-co-stimulation-and-co-5cdjz3spxg.pdf

Molecular mechanisms of T cell co-stimulation and co-inhibition

Chronic granulomatous disease. Report on a national registry of 368 patients.

Stimulation of T cell proliferation generally requires two signals: The first signal is provided by the T cell receptor binding to antigen, and the second signal or costimulus is provided by a different receptor-ligand interaction. In mouse and human, the CD28-B7 interaction has been identified as a source of costimulatory signals. We have identified a cell surface molecule (GL1) that is distinct from B7 and abundantly expressed on activated B cells. On activated B cells GL1, rather than B7, is the predominant ligand for the T cell-activation molecule CTLA-4. GL1 provides a critical signal for T cell-dependent responses in vitro and in vivo.

https://science.sciencemag.org/content/sci/262/5135/905.full.pdf

Identification of an alternative CTLA-4 ligand costimulatory for T cell activation

Global analyses of human immune variation reveal baseline predictors of postvaccination responses.

Publisher Summary This chapter discusses lymphocyte receptors for immunoglobulin (Ig) The methods used to detect lymphocyte receptors for Ig vary widely both as the type of complex utilized and the technique for measuring binding The chapter describes various techniques available The nature of the lymphocytes that bind complexed Ig are considered with reference to the sensitivity and/or specificity of the various methods A detailed consideration of lymphoid cell subpopulations, including the criteria for defining B lymphocytes, T lymphocytes, and undefined lymphocyte-like (UL) cells, is presented in the chapter Any useful Fc receptor assay system should meet certain basic criteria: (1) the percentage of lymphocytes binding Ig should be titratable to a plateau value This assumes a discontinuous distribution of receptors on different subpopulations (2) The Fc dependence of binding should be demonstrated Because the binding of Ig is dependent on the Fc portion of the molecule, this will help ensure that different assays are detecting similar receptors (3) Cells, other than lymphocytes, that bear Fc receptors should be either identified and excluded from counts or removed from the population being tested Such cells include monocytes, macrophages, neutrophils, and basophils

Lymphocyte Receptors for Immunoglobulin

By indirect immunofluorescence and microcytotoxicity it was demonstrated that different populations of murine macrophages bear different amounts of Ia antigens on their membranes. At least three subpopulations could be distinguished: those that lack Ia antigens and predominate in peritoneal exudate; cells bearing I-A antigens that are the majority of splenic macrophages and a minor population in the peritoneum; and cells bearing I-C antigens that are a minor population in both spleen and peritoneum. Internal radioisotope labeling studies confirmed that the I region molecules are synthesized by the macrophages. It is suggested that these different macrophage subpopulations may play distinct roles in the immune response.

Howard B. Dickler

Papers

Chronic granulomatous disease. Report on a national registry of 368 patients.

Identification of an alternative CTLA-4 ligand costimulatory for T cell activation

Global analyses of human immune variation reveal baseline predictors of postvaccination responses.

Lymphocyte Receptors for Immunoglobulin

Macrophage Ia Antigens I. Macrophage Populations Differ in Their Expression of Ia Antigens