Abstract
BackgroundLymphocyte infiltration is a common feature of radiation-induced pneumonitis and fibrosis, but their contribution to the pathogenic processes is still unclear. Here, we addressed the impact of thorax irradiation on the T cell compartment with a focus on immunosuppressive regulatory T cells (Treg).MethodsC57BL/6 wild type mice (WT) received anesthesia only (sham controls, 0 Gy) or were exposed to a single dose of whole thorax irradiation (15 Gy). Immune cells from lung tissue, spleen, and cervical lymph nodes were collected 10 to 84 days post-irradiation and phenotypically characterized by flow cytometry.ResultsWhole thorax irradiation provoked an increased influx of CD3+ T cells at 42 and 84 days post-irradiation. In contrast, local irradiation caused a sustained reduction in CD3+ T cells in peripheral lymphoid tissues. Interestingly, we observed a significant local and systemic increase in the fraction of CD4+ T cells expressing the transcription factor forkhead box P3 (FoxP3), the phenotypic marker for murine Treg, at day 21 post-irradiation. The accumulation of Treg was associated with increased levels of T cells expressing surface proteins characteristic for recruitment and immunosuppressive activity, e.g. CD103, CTLA-4 and CD73. Importantly, Treg isolated at this time point were able to suppress CD4+ effector T cells to a similar extent as Treg isolated from control mice.ConclusionsThe response of the adaptive immune system to whole thorax irradiation is characterized by local immunoactivation and systemic immunosuppression. The transient accumulation of immunosuppressive CD4+ FoxP3+ Treg may be required to protect the lung against excessive inflammation-induced tissue damage. Further investigations shall define the mechanisms underlying the accumulation of Treg and their role for the pathogenesis of radiation-induced lung disease.
Highlights
Radiotherapy is an integral part of current standard treatment concepts in oncology and provides a broad contribution to cancer cure alone and in combined treatment regimens
In the present investigation we addressed the potency of ionizing radiation to induce local and systemic changes in the T cell compartment with a focus on regulatory T cells (Treg) using a C57BL/6-based murine model
The fraction of B-lymphocytes (B220+ cells) in the irradiated lung tissue remained relatively constant during the early pneumonitic phase, but a significant increase in B220+ cells was detected at 84 days post-irradiation (Figure 1C)
Summary
Radiotherapy is an integral part of current standard treatment concepts in oncology and provides a broad contribution to cancer cure alone and in combined treatment regimens. Radiation-induced pneumonitis and fibrosis are observed as severe dose-limiting complications of total body irradiation (TBI) or radiotherapy of thorax-associated neoplasms [1,2,3]. There is no available effective pharmacotherapy suited to prevent or treat radiation-induced lung disease in the clinical setting so that a symptomatic antiinflammatory therapy remains standard of care, though its use is disputed [4]. Depending on the total radiation dose and the irradiated volume, patients develop a toxic inflammation of the lung parenchyma (pneumonitis) within 4 to 12 weeks post-irradiation without or with subsequent lung fibrosis. Radiation-induced lung fibrosis is mostly observed 6 to 24 months after radiotherapy and may become chronic in patients with a large irradiated lung volume [4]. We addressed the impact of thorax irradiation on the T cell compartment with a focus on immunosuppressive regulatory T cells (Treg)
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