TLR9 engagement on CD4 T lymphocytes represses γ-radiation–induced apoptosis through activation of checkpoint kinase response elements

Abstract

T cell-based therapies have much promise in cancer treatment. This approach may be enhanced if used in combination with radiotherapy provided that tumorspecific T cells can be protected against the effects of radiotherapy. Previously, we demonstrated that administration of TLR9 ligand into mice decreased activation-and serum deprivation-induced cell death in T cells. We hypothesized that TLR9 engagement on T lymphocytes decreased apoptosis after cellular stress. We show that TLR9 engagement on murine CD4 T cells reduces ␥-radiation- IntroductionThe development of T cell-based immunotherapy to treat cancer patients has advanced significantly in the last decade due to the identification of multiple tumor antigens and the understanding of the signals that stimulate antitumor T-cell responses. 1 For example, vaccine-based strategies that incorporate tumor antigens (in the form of proteins or peptides) to elicit strong CD4 and CD8 T-cell responses are effective in both the prevention and the treatment of various cancers in preclinical studies. [2][3][4] In cancer patients, infusion of in vitro-activated and expanded tumor-specific T cells has been shown to reduce tumor burden in patients with various types of malignancies. 5 Unfortunately, although T-cell responses are effective against small tumor loads, they are generally ineffective against bulky tumors. 5 One promising strategy is to combine immunotherapy with current anticancer treatments to enhance the antitumor effects.Ionizing radiotherapy (RT) is an important therapy for the treatment of tumors. 6 Generally, RT is administered locally to the tumor site or draining lymph nodes and kills cancer cells by damaging DNA. Radiotherapy is effective at reducing large burdens in some cancers and preventing local recurrence in the case of positive margins. However, RT is rarely curative as a single treatment modality and is therefore often combined with chemotherapy. Unfortunately, this combination results in the destruction of nonmalignant cells including immune cells, which are especially sensitive to radiation. 7,8 Recent reports suggest that RT and immunotherapy might have a synergistic or at least an additive effect against tumors when given sequentially. [9][10][11][12][13] There might also be an advantage of giving the treatments at the same time, provided that tumor-specific T cells can be protected against the effects of RT. 14 The use of toll-like receptor (TLR) agonists as immune adjuvants to improve antitumor T-cell responses has been a subject of intense focus in recent times. Current studies reveal that local injections of TLR agonists can be combined with RT to enhance antitumor T-cell responses; however, these mechanisms remain undefined. [9][10][11][12][13] TLRs are expressed primarily on innate immune cells and activate the immune system by recognizing a range of microbial products, including lipopolysaccharide (TLR4), peptidoglycans and lipopeptides (TLR1 and TLR2), flagellin (TLR5), RNA (TLR3, TLR7, TLR8), and unmethylated "CpG"-DNA (TLR9). 15,16 S...

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

“…Furthermore, studies by several groups, including ours, have demonstrated that activating MyD88/IRAK signaling via TLR engagement on CD4 Th cells or CD8 T cells substantially enhances proliferation (5,(21)(22)(23)(24)(25). Engagement of TLRs has also been shown to prolong cell survival, which correlates with increased expression levels of BCL-xL and BCL2 (26,27), as well as A1, and reduced levels of BIM (24,26,27).…”

When Toll-like receptor and T-cell receptor signals collide: a mechanism for enhanced CD8 T-cell effector function

“…The engagement of TLRs on APCs is a critical step for the optimal activation and expansion of T cells. However, several reports indicate that the ligation of specific TLRs directly on primary CD4 and CD8 T cells 6,7,[11][12][13]28,29 or T-cell lines 30 can enhance their responses. The study reported here was aimed at gaining a better understanding of the molecular mechanisms involved in the costimulatory effects of TLR-MyD88 activation in CD8 T cells.…”

“…1,2 However, recent advances by several groups, including ours, indicate that the adjuvant effects of certain TLR agonists may also be attributed to the activation of TLRs and the TLR adapter molecule myeloid differentiation factor (MyD88) directly in T cells. Both CD4 [3][4][5][6][7][8][9][10][11]12,13 T cells express functional TLRs. In CD8 T cells, concomitant engagement of the T-cell receptor (TCR) and TLR3 enhanced interferon-␥ (IFN-␥) production, 10 whereas TLR2 engagement on CD8 T cells increased the expression levels of granzyme B in vitro.…”

Ultraviolet Radiation Signaling through TLR4/MyD88 Constrains DNA Repair and Plays a Role in Cutaneous Immunosuppression

“…Another type of DNA damage-causing radiation, gamma irradiation, results in double-strand breaks that cannot be repaired using a complementary template; it is associated with mutagenesis and chromosome abnormalities that often lead to cell death. Repair of both UV and gamma irradiation damage was shown to be altered in the presence of endosomal TLR agonists (12,13), implying that both the NER and double-strand breaks repair complex may be affected by the status of TLR activation. In this study, we focus on DNA damage caused by UVR in the form of CBPDs, which requires NER machinery to be excised and repaired.…”