one of the most important co-stimulatory molecules expressed on T cells, CD28, which interacts predominantly with CD80 (B7.1) and CD86 (B7.2), but also with B7-H2 (ICOS-L) in humans, present on the membrane of activated APCs. It is constitutively localized, among other important T cell signaling molecules, in the central SMAC (supramolecular activation complex) of the immunological synapse. Its signaling is involved in the recruitment of proteinkinase C θ (PKCθ), Ras GEF and Ras GRP to the synapse. Moreover, it induces the activity of NFAT and NFκB transcription factors through interaction with lymphocyte cell-specific protein-tyrosine kinase (LCK) and GRB2 and/or activation of phopshoinositol-3-Kinase (PI3K) resulting in Akt kinase activation, promoting T cell proliferation and IL-2 production. Additionally, it's involved in other biochemical functions of the cell, including T cell metabolism, post-translational protein modifications or cytoskeletal remodeling. Another costimulatory receptor expressed on T cells is ICOS ( Inducible Costimulator), which interacts with ICOS-L expressed mainly on the APCs. This receptor is genetically closely related to CD28 but cannot substitute for its function. Among many similarities with CD28, it also induces Akt activity through PI3K activation and promotes proliferation. However, there are differences in these pathways, which contribute to the disparity between CD28 and ICOS signaling. Signaling through co-stimulatory molecules from TNFRSF often involves the interaction with TRAF adaptor proteins to enhance T cell stimulation. For instance, 41-BB (CD137; TNFRSF9) is a signaling molecule expressed mainly on T cells, but also on NK cells. Due to extracellular galectin 9 binding, 41-BB complexes are kept preassembled on the membrane. It interacts with TRAF1 and TRAF2 adaptor proteins, which are involved in pathway eventually leading to NFκB translocation to the nucleus, as well as MAPK/ERK pathway OX40 (CD134; TNFRSF4) is another co-stimulatory molecule expressed after T cell activation, but in the later timepoints, since it inhibits apoptosis and increases survival rate several days after the stimulation. Co-stimulation in different T cell types CD28 is important practically for all T cell types, but some other co-stimulatory molecules are expressed in some cell types more than in others. CD2 was shown to prime naive T cells (TN) even without CD28 or TCR. Also, CD27 is a receptor constituively expressed on TN (its expression is downregulated upon TCR stimulation) and enhances T cell proliferation. The differentiation of T helper cells (TH) into different subsets also partially depends on their co-stimulatory molecules. TIM1, TIM4, ICOS, CD3 or DR3 and