Ionizing radiation interacts with the immune system in many ways with a multiplicity that mirrors the complexity of the immune system itself: namely the need to maintain a delicate balance between different compartments, cells and soluble factors that work collectively to protect, maintain, and restore tissue function in the face of severe challenges including radiation damage. The cytotoxic effects of high dose radiation are less relevant after low dose exposure, where subtle quantitative and functional effects predominate that may go unnoticed until late after exposure or after a second challenge reveals or exacerbates the effects. For example, low doses may permanently alter immune fitness and therefore accelerate immune senescence and pave the way for a wide spectrum of possible pathophysiological events, including early-onset of age-related degenerative disorders and cancer. By contrast, the so called low dose radiation therapy displays beneficial, anti-inflammatory and pain relieving properties in chronic inflammatory and degenerative diseases. In this review, epidemiological, clinical and experimental data regarding the effects of low-dose radiation on the homeostasis and functional integrity of immune cells will be discussed, as will be the role of immune-mediated mechanisms in the systemic manifestation of localized exposures such as inflammatory reactions. The central conclusion is that ionizing radiation fundamentally and durably reshapes the immune system. Further, the importance of discovery of immunological pathways for modifying radiation resilience amongst other research directions in this field is implied.

The immune system plays a pivotal role in the maintenance of the integrity of an organism. Besides the protection against pathogens, it is strongly involved in cancer prevention, development and defense. This review focuses on how the immune system protects against infections and trauma and on its role in cancer development and disease. Focus is set on the interactions of the innate and adaptive immune system and tumors. The role of IFN-γ as a pleiotropic cytokine that plays a very important role at the interface of innate and adaptive immune systems in tumor development and induction of anti-tumor immune responses is outlined. Further, immune cells as prognostic and predictive markers of cancer will be discussed. Data are provided that even the brain as immune privileged organ is subjected to immune surveillance and consequently also brain tumors. Immune therapeutic approaches for glioblastoma multiforme, the most frequent and malignant brain tumor, based on vaccination with dendritic cells are outlined and application of hyperthermia in form of magnetic nanoparticles is discussed. We conclude that the immune system and developing tumors are intimately intertwined. Anti-tumor immune responses can be prominently boosted by multimodal therapies aiming on the one hand to induce immunogenic tumor cell death forms and on the other hand to actively counteract the immune suppressive microenvironment based on the tumor itself.

VDJ recombination of T cell receptor and immunoglobulin loci occurs in immature lymphoid cells. Although the molecular mechanisms of DNA cleavage and ligation have become more clear, it is not understood what controls which target loci undergo rearrangement. In interleukin 7 receptor (IL-7R)α^−/− murine thymocytes, it has been shown that rearrangement of the T cell receptor (TCR)-γ locus is virtually abrogated, whereas other rearranging loci are less severely affected. By examining different strains of mice with targeted mutations, we now observe that the signaling pathway leading from IL-7Rα to rearrangement of the TCR-γ locus requires the γ_c receptor chain and the γ_c-associated Janus kinase Jak3. Production of sterile transcripts from the TCR-γ locus, a process that generally precedes rearrangement of a locus, was greatly repressed in IL-7Rα^−/− thymocytes. The repressed transcription was not due to a lack in transcription factors since the three transcription factors known to regulate this locus were readily detected in IL-7Rα^−/− thymocytes. Instead, the TCR-γ locus was shown to be methylated in IL-7Rα^−/− thymocytes. Treatment of IL-7Rα^−/− precursor T cells with the specific histone deacetylase inhibitor trichostatin A released the block of TCR-γ gene rearrangement. This data supports the model that IL-7R promotes TCR-γ gene rearrangement by regulating accessibility of the locus via demethylation and histone acetylation of the locus.

To ascertain how the actual repertoire of T cell receptors (TCRs) deviates from the theoretical, we have generated a large number of junctional region sequences from TCRs carrying the V beta 17 variable region. The greater than 600 sequences analyzed represent transcripts from nine different cell populations, permitting several comparisons: transcripts from an expressed vs. a non-expressed V beta 17 allele, those from E+ vs. E- mice, transcripts from immature vs. mature thymocytes, those from thymic vs. peripheral T cells, and those from CD4+ vs. CD8+ cells. These comparisons have allowed us to distinguish between the influence of molecular events involved in TCR gene rearrangement and that of various selection events that shape the T cell repertoire. Our most striking findings are: (a) that J beta usage is markedly skewed, partly due to recombination mechanics and partly due to selection forces: in particular, those mediated by the class II E molecule in the thymus; and (b) that TCRs on CD4+ and CD8+ cells show intriguing dissimilarities. In addition, we present evidence that N nucleotide additions occur with clear biases, probably due to idiosyncrasies of the recombination enzymes, and provide arguments that TCR and immunoglobulin CDR3s have distinct structures.

Organisms respond to physical, chemical and biological threats by a potent inflammatory response, aimed at preserving tissue integrity and restoring tissue homeostasis and function. Systemic effects in an organism refer to an effect or phenomenon which originates at a specific point and can spread throughout the body affecting a group of organs or tissues. Ionizing radiation (IR)-induced systemic effects arise usually from a local exposure of an organ or part of the body. This stress induces a variety of responses in the irradiated cells/tissues, initiated by the DNA damage response and DNA repair (DDR/R), apoptosis or immune response, including inflammation. Activation of this IR-response (IRR) system, especially at the organism level, consists of several subsystems and exerts a variety of targeted and non-targeted effects. Based on the above, we believe that in order to understand this complex response system better one should follow a ‘holistic’ approach including all possible mechanisms and at all organization levels. In this review, we describe the current status of knowledge on the topic, as well as the key molecules and main mechanisms involved in the ‘spreading’ of the message throughout the body or cells. Last but not least, we discuss the danger-signal mediated systemic immune effects of radiotherapy for the clinical setup.