In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. and by direct exchange of molecules gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. and studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy. cell-to-cell connecting channels. These factors act as damaging agents or signaling molecules and can affect other cells in a paracrine or endocrine manner. Radiation-induced bystander effects have been first described by Nagasawa and Little in an experiment, where only a small fraction of the cells ( 1%) were traversed by an -particle, but more than 30% of the whole cell population showed damages (37). At present time, damages by RIBE GU2 are characterized as DNA damage, chromosome aberrations, sister-chromatid exchanges, genomic instability, and cellular senescence. Among the damaging agents are ROS and reactive nitrogen species (RNS)?(38, 39). Radiation-induced bystander effects are not only an indirect way for ionizing radiation to cause destruction. The secretion of signaling factors bio-THZ1 of this particular bio-THZ1 cellular response can also protect cells from further damages by preenhancing repair mechanisms or lead to a faster clean-up of radiation-damaged cells (40C42). The most prominent signaling molecules in RIBE are factors triggering an immune response. Part of the damage response of an irradiated cell is the activation of the transcription factor nuclear factor B (NF-B) (43). Downstream of NF-B activation, chemokines and cytokines are produced and secreted, which can attract and stimulate cells of the immune system. Besides cytokine and chemokine secretion, cells can communicate extracellular vesicles or exosomes. These membrane-coated bodies can contain a multitude of factors ranging from proteins to micro-RNA that can modulate cellular functions and induce signaling pathways. After secretion of the vesicles into the extracellular space, exosomes can affect neighboring cells by binding to surface receptors or by uptake and intracellular release of their content. Exosomes in RIBE have been associated with DNA damage, survival, proliferation, and signal transduction, resulting from the variety of factors carried within and the possible ways to impact recipient cells (44C52). The influence of ionizing radiation on composition and secretion of exosomes was recently reviewed by Jelonek et al. bio-THZ1 (49). In the innate immune response, recognition of pathogen-associated molecular patterns or damage-associated molecular patterns (DAMPs) by germline-coded cell surface or intracellular receptors [pattern recognition receptors (PRRs)] is the central trigger of activation. In the adaptive immune response, antigen presentation by APCs to T- and B-lymphocytes is the central process for their activation. Antigens are bound to major histocompatibility complex class I (MHC-I) molecules on the surface of body cells and to MHC class II (MHC-II) molecules on APCs [in humans: MHC class Ia C human leukocyte antigen (HLA)-A, -B and -C; MHC class Ib C HLA-E, -F-, -G; MHC class II?C HLA-DM, -DO, -DP, -DQ, -DR]. Antigen recognition by T helper cells and B-cells or CTL in combination with co-stimulation, intercellular adhesion and stimulation by cytokines results in their activation. Therefore, radiation induced modifications of these intercellular communication pathways are of utmost importance in the non-targeted response of the immune system. Radiation-induced bystander effects in the immune.