Radiation-induced pneumonitis and fibrosis still constitute a major complication in the treatment of patients with thorax-associated neoplasms. To date, the molecular mechanisms governing the onset and progression of these injuries are not entirely understood and no effective therapies are available. Aim of the present study was to gain more insight into the pathogenesis of radiation-induced pneumonitis and fibrosis, with the ultimate goal to provide a molecular basis for the development of novel and effective strategies for prevention or treatment of these pathologies. At this purpose, investigations on immune cells and on immunomodulatory molecules have been performed in vivo in a C57BL/6 mouse model of whole thorax irradiation with 15 Gray (Gy). In the present work, a novel immunoregulatory molecule was identified as a key mediator of radiation-induced fibrosis, in that mice deficient in this molecule showed no or minimal fibrosis at 30 weeks post irradiation (p.i.), while wild type (WT) mice showed extensive collagen deposition, and fibrotic areas positive for α-SMA and TGF-β at this time point. Thus, lack of this molecule seems to exert a radioprotective effect. Of note, the progression to a more pronounced fibrosis in WT mice was associated with altered expression of this molecule on immune cells during the pneumonitic phase, and with early and late changes in the composition and phenotype of immune cells, both locally and systemically. Thus, endogenous presence or absence of this immunoregulatory molecule results in distinct responses within the lung tissue, determining the progression and the final outcome of radiation-induced side effects. Remarkably, complete absence of mature B and T cells led to an increased sensitivity to radiation-induced fibrosis. This model provided evidence for a direct involvement of the immune system in the pathogenesis of lung radiation-induced pneumopathy. Regulation of the immune system during lung responses to ionizing radiation might therefore represent a good target for future treatments.