2-Gy whole-body irradiation significantly alters the balance of CD4+CD25−T effector cells and CD4+CD25+Foxp3+T regulatory cells in mice

Qu, Yanyan; Zhang, Baojun; Liu, Shuchun; Zhang, Aijun; Wang, Tingting; Zhao, Yong

doi:10.1038/cmi.2010.45

Cited by 63 publications

(53 citation statements)

References 52 publications

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“…Although there were main eff ects of radiation in all three of the cytokines we assessed, these eff ects only occurred in the E. coli -treated mice and will be discussed below. A lack of a signifi cant response in these cytokines after radiation alone is consistent with a previous report by Qu et al (2010) using reverse transcription polymerase chain reaction (RT-PCR) to assess several cytokines. In that study, there were minimal changes in splenic IL-6 and TNF-α 1 -3 days after 2 Gy gamma-irradiation.…”

Section: Oxidative Burstsupporting

confidence: 87%

“…So their increase in response to E. coli is not surprising. However, these cytokine are primarily released by activated macrophages, T cells and B cells, all shown to be reduced by radiation here and elsewhere , 2003a, Pecaut and Gridley 2008, Qu et al 2010. Furthermore, radiation did not appear to have any eff ect on these cytokines in the absence of an immune challenge.…”

Section: Oxidative Burstmentioning

confidence: 79%

“…We and others have reported decreases in all major leukocyte and lymphocyte subsets 2 -14 days after relatively low doses of low linear energy transfer (LET) irradiation, including both gammarays , Pecaut and Gridley 2008, Qu et al 2010, Mehrotra et al 2013 and protons , 2003b, 2003c, Gridley and Pecaut 2006. Th is suggests that radiation would have an immediate impact on the response to infection.…”

Section: Introductionmentioning

confidence: 97%

See 2 more Smart Citations

Impact of total-body irradiation on the response to a live bacterial challenge

Pecaut¹,

Baqai²,

Gridley³

2014

International Journal of Radiation Biology

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Section: Oxidative Burstsupporting

confidence: 87%

Section: Oxidative Burstmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 97%

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Impact of total-body irradiation on the response to a live bacterial challenge

Pecaut¹,

Baqai²,

Gridley³

2014

International Journal of Radiation Biology

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“…In addition to killing radiosensitive immune cells, ionizing radiation can induce microenvironmental changes in the tumor milieu and thereby regulate the Th1/Th2 balance (3). It has been observed that whole-body irradiation with c rays decreases the lymphocyte pool significantly, and that various lymphocyte populations have variable sensitivities to c radiation (4,5). Early reports showing that radiation exposure could slow the growth of transplanted tumors through the enhancement of the anticancer immune response in total-body irradiation mouse model (6), drew attention toward the use of radiation as an immunological adjuvant to enhance tumor control.…”

Section: Introductionmentioning

confidence: 99%

In SituObservation of the Effects of Local Irradiation on Cytotoxic and Regulatory T Lymphocytes in Cervical Cancer Tissue

et al. 2013

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Local radiotherapy is the major therapeutic approach to control inoperable cervical cancer. In this study, we analyzed the local immune microenvironment of cervical cancer before and after clinical radiation therapy to investigate whether tumor response due to immunomodulation. A total of 59 patients with pathologically diagnosed cervical cancers classified according to the International Federation of Obstetrics and Gynecology (FIGO) criteria were recruited. The patients were treated according to their disease status with standard radiation regimens. For each patient, tumor biopsies were conducted before, during and after radiation treatment with the doses of 0, 10, 20 and 30 Gy, respectively. All of the tumor samples were then grouped according to the doses delivered and tumor infiltrating lymphocytes with the biomarkers of CD8, CD4, FOXP3 and OX40 were measured by in situ immunohistochemistry. We found that before radiation treatment both CD8(+) T cell and CD4(+) T cell infiltrates were more present in the tumor stroma than in the tumor nests, while OX40(+) and FOXP3(+) T cell infiltrates were present at similar levels in both the tumor nests and stroma. After radiation treatment, the levels of CD8(+) T cells and CD4(+) T cells in the tumor nests and stroma were decreased compared with the levels before irradiation. However, OX40(+) T cells and FOXP3(+) T cells did not show any difference before and after irradiation, which indicates that the FOXP3(+) T cells were more resistant to ionizing radiation than were the cytotoxic effector T cells and demonstrates a dynamic rebalance of infiltrating lymphocytes in the tumor milieu occurs after radiotherapy. This suggest that local antitumor immunity could be compromised due to decreased cytotoxic effector cells and the relatively stable status of FOXP3(+) T cells after irradiation. Therefore, regulation of these FOXP3(+) T cells may be a potentially effective approach to enhance the efficacy of cancer radiation therapy.

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“…This suggests a similar breakdown of checkpoint regulation, plausibly due to an IL-2/αIL-2-mediated effect on insulinreactive T cells, which are prominent in 6-week old NOD mice, or other potentially diabetogenic immune cells. Some evidence suggests lymphopenia, observed in the present study, is detrimental for tolerance induction due to the reduced recovery of Treg (Kaminitz et al, 2010), although, other studies have suggested Treg are less susceptible to irradiation-induced apoptosis (Qu et al, 2010a;Qu et al, 2010b). The effect of irradiation-induced lymphopenia may contribute to the different effects of proinsulin-encoding BM/HSPC transfer on diabetes development at different disease stages.…”

Section: Discussionmentioning

confidence: 38%

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

Reeves¹

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Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β cells. The current treatment for the fatal insulin-deficiency in T1D is injection of exogenous insulin. Despite the dramatic increase in survival from the use of exogenous insulin, complications develop from imperfect glycemic control and exogenous insulin does not rectify the underlying cause of disease, the diabetogenic autoimmune response. Hence, there is a need for an effective therapy that impedes the progress of the pathogenic autoimmune response. β cell-reactive CD8 + In the NOD mouse model of T1D, insulin is the primary β-cell antigen that elicits disease. As such, I have investigated T-cell tolerance to insulin in an adoptive transfer setting in which TCR transgenic (G9) CD8 + T cells specific for insulin B15-23 (InsB15-23) were transferred to transgenic mice over-expressing proinsulin in APC. Subsequently, I examined the effect of introducing transgenic proinsulin expression on diabetes development in wild type NOD mice.When transferred to mice transgenically expressing proinsulin, naïve G9 T cells proliferated extensively prior to undergoing rapid deletion. In proinsulin transgenic recipients, the remaining population of G9 T cells displayed reduced T-cell receptor (TCR) expression and bound less InsB15-23-loaded, H2-K d -tetramer compared to G9 T cells that had been transferred to non-transgenic NOD recipients. Interestingly, TCR down-regulation represented that which occurred for OVA-specific CD8 + T cells transferred to mice expressing OVA in APC in a non-autoimmune prone strain.Importantly, naïve G9 T cells did not expand or produce the important effector cytokine, interferon (IFN)-γ, in response to InsB15-23 immunisation after transfer to proinsulin transgenic mice. These data confirm naïve G9 T cells undergo rapid deletion and inactivation after transfer to mice transgenically-expressing proinsulin, despite genetic tolerance defects in NOD mice. Memory CD8 + T cells (Tmem) perpetuate β-cell autoimmunity and pose a distinct barrier to immunotherapy. It was pertinent to determine whether inactivation of insulin-specific CD8 + Tmem also occurs after transfer to mice expressing proinsulin in APC. To test inactivation of insulin-specific CD8 + Tmem, G9 Tmem were generated using an in vitro culture method. Cultured G9 Tmem were validated by assessing phenotypic markers and cytokine production. Similarly to naïve G9 T cells, G9 Tmem proliferated extensively and most G9 Tmem were rapidly deleted after transfer to mice overexpressing proinsulin in APC. The remaining, non-deleted population of G9 Tmem was infrequent ii and exhibited reduced TCR expression. Furthermore, G9 Tmem did not expand or produce IFN-γ in response to InsB15-23 immunisation, consistent with functional inactivation. These results demonstrate transgenic proinsulin expression in APC overcomes genetic defects in NOD mice to induce tolerance in insulin-specific CD8 + Tmem.From the data described above, transgenic proinsulin expression is tolerogenic for in...

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2-Gy whole-body irradiation significantly alters the balance of CD4+CD25−T effector cells and CD4+CD25+Foxp3+T regulatory cells in mice

Cited by 63 publications

References 52 publications

Impact of total-body irradiation on the response to a live bacterial challenge

Impact of total-body irradiation on the response to a live bacterial challenge

In SituObservation of the Effects of Local Irradiation on Cytotoxic and Regulatory T Lymphocytes in Cervical Cancer Tissue

Transgenic expression of proinsulin to inactivate insulin-specific CD8+ T-cell responses in autoimmune diabetes

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