Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors. T cell co-stimulation T cells require two signals to become fully activated. A first signal, which is antigen-specific, is provided through the T cell receptor (TCR) which interacts with peptide-MHC molecules on the membrane of an antigen presenting cell (APC). A second signal, the co-stimulatory signal, is antigen nonspecific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of the APC and the T cell. This interaction promotes and enhances the TCR signaling, but can also be bi-directional. The co-stimulatory signal is necessary for T cell proliferation, differentiation and survival. Activation of T cells without co-stimulation may lead to the unresponsiveness of the T cell (also called anergy), apoptosis or the acquisition of the immune tolerance. The counterpart of the co-stimulatory signal is a (co-)inhibitory signal, where inhibitory molecules interact with different signaling pathways in order to arrest T cell activation. Mostly known inhibitory molecules are CTLA4 and PD1, used in cancer immunotherapy. In T cell biology there are several co-stimulatory molecules from different protein families. Mostly studied are those belonging to Immunoglobulin super-family (IgSF) (such as CD28, B7, ICOS, CD226 or CRTAM) and TNF receptor super-family (TNFRSF) (such as 41-BB, OX40, CD27, GITR, HVEM, CD40, BAFFR, BAFF and others). Additionally, some co-stimulatory molecules belong to TIM family, CD2/SLAM family or BTN/BTN-like family. The surface expression of different co-stimulatory molecules is regulated on a transcriptional and post-transcriptional level, but also by endocytosis. The dynamics of the receptor expression usually depends on the cell state. Some molecules are permanently expressed on non-stimulated cells, such as CD28, others only after TCR triggering, for example 41-BB or CD27. Mechanism of function Generally, the mechanism of function of co-stimulatory molecules is based on the overlap of their signaling pathway with the primary (TCR) signal and the induction of other, distal pathways often using different routes, leading to the enhancement of TCR signal and expression of effector genes. Additionally, co-stimulatory signaling can also have a unique outcome. The example of IgSF molecule is