several molecules from the SLAM family were shown to induce polarization towards TH2. In contrast, CD27 and HVEM promote TH1 polarization. OX40 and ICOS expression was linked to T folicular helper (TFH) differentiation and maintenance. Regulatory T cells (TREG) need CD28 signal for their 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 enhance 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. B cell co-stimulation B cell binds antigens with its BCR (a membrane-bound antibody), which transfers intracellular signals to the B cell as well as inducing the B cell to engulf the antigen, process it, and present it on the MHC II molecules. The latter case induces recognition by antigen-specific Th2 cells or Tfh cells, leading to activation of the B cell through binding of TCR to the MHC-antigen complex. It is followed by synthesis and presentation of CD40L (CD154) on the Th2 cell, which binds to CD40 on the B cell, thus the Th2 cell can co-stimulate the B cell. Without this co-stimulation the B cell cannot proliferate further. Co-stimulation for B cells is provided alternatively by complement receptors. Microbes may activate the complement system directly and complement component C3b bind to microbes. After C3b is degraded into a fragment iC3b (inactive derivative of C3b), then cleaved to C3dg, and finally to C3d, which continue to bind to microbial surface, B cells express complement receptor CR2 (CD21) to bind to iC3b, C3dg, or C3d. This additional binding makes the B cells 100- to 10,000-fold more sensitive to antigen. CR2 on mature B cells forms a complex with CD19 and CD81. This complex is called the B cell coreceptor complex for such sensitivity enhancement to the antigen. Applications Abatacept (Orencia) is a T cell co-stimulation modulator approved for the treatment of rheumatoid arthritis. The cytokines secreted by activated T cells are thought to both initiate and propagate the immunologically driven inflammation associated with rheumatoid arthritis. Orencia, a soluble fusion protein, works by altering the co-stimulatory signal required for full T-cell activation. Belatacept is another novel molecule which