User:MichaelaCesnekova/sandbox

This is my new sandbox

T cell Costimulation
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 cells (APC). A second signal, the co-stimulatory signal, is antigen nonspecific and is provided by the interaction between the 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 co-stimulatory signal is (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 a non-stimulated cells, such as CD28 or only after TCR triggering, for example 41-BB or CD27.

Mechanism
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 signalling also can lead to unique outcome.

The example of IgSF molecule is one of the most important co-stimulatory molecules expressed by T cells is 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 an APC. 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. Also, it induces the activity of NFAT and NFκB transcription factors via interaction with lymphocyte cell-specific protein-tyrosine kinase (LCK) and GRB2 and/or activation of phopshoinositide-3-kinase (PI3K) resulting in Akt kinase activation, promoting T cell proliferation and IL-2 production. Additionally, it is involved in other biochemical functions of the cell, including T cell metabolism, post-translational modifications or cytoskeletal remodeling

Another costimulatory receptor from IgSF is ICOS ( Inducible Costimulator), which interacts with ICOS-L expressed mainly on the APCs. This receptor is genetically closely related to CD28 but cannot substitue 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 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. Thanks 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, as it inhibits apoptosis and increases survival rate several days after the stimulation.

Co-stimulation molecules in different T cell types
CD28 is important practically for all T cell types, but some other 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 several molecules from the SLAM family were shown to induce polarization towards TH2. Converesely, CD27 and HVEM promote TH1 polarization. OX40 and ICOS expression was linked to T folicular helper (TFH) differentiation and maintenance. T regulatory cells (TREG) need CD28 signal for generation and ICOS signal for their peripheral maintenance and survival. In contrast, HVEM, GITR and CD30 are suppressing their activity.

Effector T cells are mainly regulated by TNFRSF molecules, such as 41-BB, CD27, OX40, DR3 or GITR, which ehance their proliferation and survival.

Memory T cells (TM) were also shown to necessitate co-stimulatory signals. Apart from CD28, ICOS, 41-BB, OX40, TIM3, CD30, BTLA or CD27 were also shown to play role in the proper formation and later signaling of TM.