[CD28 costimulation and checkpoint inhibition in T cells]. / CD28-Kostimulation und Checkpointblockade in T-Zellen.

BACKGROUND: The induction of protective T cell responses requires two signals: Signal 1 is generated by activation of the T cell receptor (TCR) and signal 2 results from ligation of the CD28 molecule. Costimulation of the TCR and CD28 is necessary, as the TCR is very good at discriminating between endogenous and foreign structures (antigens), but not all foreign antigens (such as food antigens) are dangerous to the body. A strong CD28 signal, thus, indicates to the T cell that there is indeed a threat and that an immune response is urgently required. However, to avoid autoimmunity and excessive immune responses, further regulatory circuits, provided by immune checkpoints, are necessary. OBJECTIVES: To provide an introduction to immunoregulation mediated by checkpoint molecules. MATERIALS AND METHODS: Review of basic science papers and reports on clinical studies. RESULTS: The most prominent and best characterized checkpoint molecules, cytotoxic T lymphocyte-associated protein­4 (CTLA-4) and programmed cell death­1 (PD-1), both physiologically dampen CD28-mediated costimulation. Pathologically, malignancies exploit the immunoregulatory function of checkpoint molecules by, for example, expressing ligands for PD­1 on the cell surface, thus, avoiding being attacked by T cells. Our understanding of these negative feedback regulations has led to the development of checkpoint inhibitors, which have already become part of routine clinical care of cancer patients. CONCLUSIONS: Due to the clinical success of checkpoint inhibitors, the concept of cancer immunotherapy has received a massive boost and hopes are high that many more clinical advancements in cancer therapy can be achieved with novel forms of immunotherapy.

Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases.

This paper reviews the existing evidence regarding the use of superagonistic anti-CD28 antibodies (CD28 superagonists) for therapeutic manipulation of regulatory T cells (T(reg) cells). The molecular properties of superagonistic anti-CD28 antibodies allow the generation of a strong activating signal in mature T cells, including T(reg) cells, without additional stimulation of the T cell receptor complex. CD28 superagonist administration in vivo leads to the preferential expansion and strong activation of naturally occurring CD4+CD25+CTLA-4+FoxP3+ T(reg) cells over conventional T cells. In animal models, both prophylactic and therapeutic administration of a CD28 superagonist prevented or at least greatly mitigated clinical symptoms and induced remission. Adoptive transfer experiments have further shown that CD28 superagonists mediate protection by expansion and activation of CD4+CD25+ T(reg) cells. Therefore, superagonistic anti-CD28 antibodies offer a promising novel treatment option for human autoimmune diseases and the first clinical trials are eagerly awaited.

Expression of inhibitory "killer cell lectin-like receptor G1" identifies unique subpopulations of effector and memory CD8 T cells.

T cell and natural killer (NK) cell functions are regulated by triggering of activating and inhibitory cell surface receptors. Here, we have studied the expression profile and predicted inhibitory function of mouse "killer cell lectin-like receptor G1" (KLRG1) on CD8 T cells. KLRG1 was present on 1 - 3 % of adult splenic CD8 cells that expressed CD8alpha beta heterodimers as well as a polyclonal TCR Vbeta repertoire indicative of conventional CD8 cells. The majority of KLRG1(+) CD8 cells belonged to the memory pool as determined by extensive phenotypic marker analysis. Spontaneous IFN-gamma production by approximately 20 % of KLRG1(+) CD8 cells identified them as pro-inflammatory effector cells. In contrast to NK cells, Ly49 and KLRG1 expression on CD8cells was found to be mutually exclusive. Therefore, distinct programs regulate KLRG1 expression in CD8 and NK cells. Finally, we provide evidence that KLRG1 triggering interferes with TCRalpha beta-mediated Ca(++) mobilization and cytotoxicity, raising the possibility that KLRG1 functionally participates in down-regulation of CD8 T cell responses.