T cell costimulation, checkpoint inhibitors and anti-tumor therapy.

The hallmarks of the adaptive immune response are specificity and memory. The cellular response is mediated by T cells which express cell surface T cell receptors (TCRs) that recognize peptide antigens in complex with major histocompatibility complex (MHC) molecules on antigen presenting cells (APCs). However, binding of cognate TCRs with MHC-peptide complexes alone (signal 1) does not trigger optimal T cell activation. In addition to signal 1, the binding of positive and negative costimulatory receptors to their ligands modulates T cell activation. This complex signaling network prevents aberrant activation of T cells. CD28 is the main positive costimulatory receptor on nai¨ve T cells; upon activation, CTLA4 is induced but reduces T cell activation. Further studies led to the identification of additional negative costimulatory receptors known as checkpoints, e.g. PD1. This review chronicles the basic studies in T cell costimulation that led to the discovery of checkpoint inhibitors, i.e. antibodies to negative costimulatory receptors (e.g. CTLA4 and PD1) which reduce tumor growth. This discovery has been recognized with the award of the 2018 Nobel prize in Physiology/Medicine. This review highlights the structural and functional roles of costimulatory receptors, the mechanisms by which checkpoint inhibitors work, the challenges encountered and future prospects.

A quantitative assessment of costimulation and phosphatase activity on microclusters in early T cell signaling.

T cell signaling is triggered through stimulation of the T cell receptor and costimulatory receptors. Receptor activation leads to the formation of membrane-proximal protein microclusters. These clusters undergo tyrosine phosphorylation and organize multiprotein complexes thereby acting as molecular signaling platforms. Little is known about how the quantity and phosphorylation levels of microclusters are affected by costimulatory signals and the activity of specific signaling proteins. We combined micrometer-sized, microcontact printed, striped patterns of different stimuli and simultaneous analysis of different cell strains with image processing protocols to address this problem. First, we validated the stimulation protocol by showing that high expression levels CD28 result in increased cell spreading. Subsequently, we addressed the role of costimulation and a specific phosphotyrosine phosphatase in cluster formation by including a SHP2 knock-down strain in our system. Distinguishing cell strains using carboxyfluorescein succinimidyl ester enabled a comparison within single samples. SHP2 exerted its effect by lowering phosphorylation levels of individual clusters while CD28 costimulation mainly increased the number of signaling clusters and cell spreading. These effects were observed for general tyrosine phosphorylation of clusters and for phosphorylated PLCγ1. Our analysis enables a clear distinction between factors determining the number of microclusters and those that act on these signaling platforms.

NPY suppressed development of experimental autoimmune encephalomyelitis in Dark Agouti rats by disrupting costimulatory molecule interactions.

Neuropeptide Y (NPY) suppressed clinical experimental autoimmune encephalomyelitis (EAE) and reduced numbers of CD28+, CD11b+ and CD80+ cells among spinal cord infiltrating cells at the peak of disease in Dark Agouti rat strain. Suppression of EAE was accompanied by the reduced expression of costimulatory CD80 and CD86 molecules on ED1+ macrophages and OX62+ dendritic cells in draining lymph nodes during the inductive phase of EAE. An inhibitor of dipeptidyl peptidase 4, an enzyme which terminates the action of NPY on Y1 receptor subtype, did not sustain the suppressive effect of NPY on the EAE development, suggesting involvement of Y2 and Y5 receptors.

T-cell activation and transplantation tolerance.

Transplantation of allogeneic or "nonself" tissues stimulates a robust immune response leading to graft rejection, and therefore, most recipients of allogeneic organ transplants require the lifelong use of immune suppressive agents. Excellent outcomes notwithstanding, contemporary immunosuppressive medications are toxic, are often not taken by patients, and pose long-term risks of infection and malignancy. The ultimate goal in transplantation is to develop new treatments that will supplant the need for general immunosuppression. Here, we will describe the development and application of costimulation blockade to induce transplantation tolerance and discuss how the diverse array of signals that act on T cells will determine the balance between graft survival and rejection.

[T-cell costimulation. Basic mechanisms and new aspects]. / T-Zell-Kostimulation. Grundlegende Mechanismen und neue Entwicklungen.

Recent publications regarding the function of the T-cell costimulators CD226 and TIGIT as well as the identification of the new costimulatory ligand VISTA are of great interest for an understanding of autoimmune diseases. Both systems display striking similarities to the well-established costimulators CD28/CTLA-4 and PD-1.