CD47 promotes peripheral T cell survival by preventing dendritic cell-mediated T cell necroptosis.

Conventional dendritic cells (cDCs) are required for peripheral T cell homeostasis in lymphoid organs, but the molecular mechanism underlying this requirement has remained unclear. We here show that T cell-specific CD47-deficient (Cd47 ΔT) mice have a markedly reduced number of T cells in peripheral tissues. Direct interaction of CD47-deficient T cells with cDCs resulted in activation of the latter cells, which in turn induced necroptosis of the former cells. The deficiency and cell death of T cells in Cd47 ΔT mice required expression of its receptor signal regulatory protein α on cDCs. The development of CD4+ T helper cell-dependent contact hypersensitivity and inhibition of tumor growth by cytotoxic CD8+ T cells were both markedly impaired in Cd47 ΔT mice. CD47 on T cells thus likely prevents their necroptotic cell death initiated by cDCs and thereby promotes T cell survival and function.

SIRPα on CD11c+ cells induces Th17 cell differentiation and subsequent inflammation in the CNS in experimental autoimmune encephalomyelitis.

Signal regulatory protein α (SIRPα) is expressed predominantly on type 2 conventional dendritic cells (cDC2s) and macrophages. We previously showed that mice systemically lacking SIRPα were resistant to experimental autoimmune encephalomyelitis (EAE). Here, we showed that deletion of SIRPα in CD11c+ cells of mice (SirpaΔDC mice) also markedly ameliorated the development of EAE. The frequency of cDCs and migratory DCs (mDCs), as well as that of Th17 cells, were significantly reduced in draining lymph nodes of SirpaΔDC mice at the onset of EAE. In addition, we found the marked reduction in the number of Th17 cells and DCs in the CNS of SirpaΔDC mice at the peak of EAE. Whereas inducible systemic ablation of SIRPα before the induction of EAE prevented disease development, that after EAE onset did not ameliorate the clinical signs of disease. We also found that EAE development was partially attenuated in mice with CD11c+ cell-specific ablation of CD47, a ligand of SIRPα. Collectively, our results suggest that SIRPα expressed on CD11c+ cells, such as cDC2s and mDCs, is indispensable for the development of EAE, being required for the priming of self-reactive Th17 cells in the periphery as well as for the inflammation in the CNS.

SIRPα+ dendritic cells promote the development of fibroblastic reticular cells in murine peripheral lymph nodes.

Nonhematopoietic stromal cells contribute to the organization and homeostasis of secondary lymphoid organs by producing cytokines and chemokines. The development and maintenance of these stromal cells are thought to be regulated by innate immune cells. Indeed, we recently showed that signal regulatory protein α (SIRPα)-positive dendritic cells (DCs) are essential for the proliferation and survival of podoplanin (Pdpn)-positive fibroblastic reticular cells (FRCs) in mouse spleen. We have now established an in vitro culture system for lymph node stromal cells (LNSCs) isolated from mouse peripheral LNs. Activated DCs and TNF-α each promoted the proliferation of cultured LNSCs, most of which were found to be Pdpn+ FRCs. Furthermore, ablation of SIRPα in CD11c+ cells attenuated this effect of DCs on LNSC proliferation. Transplantation of activated DCs together with cultured LNSCs into the renal subcapsular space markedly increased the number of ER-TR7+ stromal cells as well as induced the accumulation of T cells and increased the expression of Ccl19 in the transplants. Ablation of SIRPα in CD11c+ cells greatly impaired the development of LN-like structure in the transplants. Our findings thus suggest that SIRPα+ DCs are important for the proliferation and differentiation of Pdpn+ FRCs in peripheral LNs.

SIRPα+ dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen.

In secondary lymphoid organs, development and homeostasis of stromal cells such as podoplanin (Pdpn)-positive fibroblastic reticular cells (FRCs) are regulated by hematopoietic cells, but the cellular and molecular mechanisms of such regulation have remained unclear. Here we show that ablation of either signal regulatory protein α (SIRPα), an Ig superfamily protein, or its ligand CD47 in conventional dendritic cells (cDCs) markedly reduced the number of CD4+ cDCs as well as that of Pdpn+ FRCs and T cells in the adult mouse spleen. Such ablation also impaired the survival of FRCs as well as the production by CD4+ cDCs of tumor necrosis factor receptor (TNFR) ligands, including TNF-α, which was shown to promote the proliferation and survival of Pdpn+ FRCs. CD4+ cDCs thus regulate the steady-state homeostasis of FRCs in the adult spleen via the production of TNFR ligands, with the CD47-SIRPα interaction in cDCs likely being indispensable for such regulation.

Dendritic cell SIRPα regulates homeostasis of dendritic cells in lymphoid organs.

Signal regulatory protein α (SIRPα), an immunoglobulin superfamily protein that is expressed predominantly in myeloid lineage cells such as dendritic cells (DCs) or macrophages, mediates cell-cell signaling. In the immune system, SIRPα is thought to be important for homeostasis of DCs, but it remains unclear whether SIRPα intrinsic to DCs is indeed indispensable for such functional role. Thus, we here generated the mice, in which SIRPα was specifically ablated in CD11c(+) DCs (Sirpa(Δ) (DC) ). Sirpa(Δ) (DC) mice manifested a marked reduction of CD4(+) CD8α(-) conventional DCs (cDCs) in the secondary lymphoid organs, as well as of Langerhans cells in the epidermis. Such reduction of cDCs in Sirpa(Δ) (DC) mice was comparable to that apparent with the mice, in which SIRPα was systemically ablated. Expression of SIRPα in DCs was well correlated with that of either endothelial cell-selective adhesion molecule (ESAM) or Epstein-Barr virus-induced molecule 2 (EBI2), both of which were also implicated in the regulation of DC homeostasis. Indeed, ESAM(+) or EBI2(+) cDCs were markedly reduced in the spleen of Sirpa(Δ) (DC) mice. Thus, our results suggest that SIRPα intrinsic to CD11c(+) DCs is essential for homeostasis of cDCs in the secondary lymphoid organs and skin.

Lag time, high-risk histopathological features, metastasis, and survival interrelation in retinoblastoma: a perspective from lower-middle income country.

AIM: To investigate the impact of lag time to metastasis and survival rates among patients with retinoblastoma. METHODS: This retrospective study was conducted with 52 patients from the Department of Ophthalmology and the Department of Pediatrics of Dr. Sardjito General Hospital, between 1st January 2014 and 31st December 2020. Lag time was defined as the time delay between the first sign of retinoblastoma to the diagnosis of retinoblastoma. The subjects with lag time > one year were included in the case group, while the subjects with lag time < one year were included in the control group. RESULTS: The lag time was significantly correlated with American Joint Committee on Cancer and Intraocular Classification of Retinoblastoma staging of retinoblastoma (P=0.005 and P=0.006, respectively). The lag time was also significantly correlated with both metastasis event [odds ratio (OR): 5.06, 95%Cl: 1.56-16.44, P=0.006] and mortality (OR: 4.54, 95%Cl: 1.37-15.07, P=0.011). The follow-up was continued for 32 subjects for 3y after initial diagnoses. Survival analysis revealed a significant difference among these two groups (P=0.021). Furthermore, lag time was significantly correlated with survival of retinoblastoma (r=-0.53, P=0.046). CONCLUSION: The study highlights the importance of lag time between the onset of first symptoms and the time of retinoblastoma diagnosis which significantly contribute to metastasis and mortality of patients with retinoblastoma. Examinations for the early detection of retinoblastoma should be performed for individuals at-risk to minimize lag time and improve the outcomes.

Relationships Between Neurofibromatosis-2, Progesterone Receptor Expression, the Use of Exogenous Progesterone, and Risk of Orbitocranial Meningioma in Females.

Background: The pathogenesis of meningioma in females and its association with exogenous progesterone is remained unclear. This study was aimed to examine expression of Progesterone receptor (PR) and Neurofibromatosis-2 (NF2) and assess their relationships to history of exogenous progesterone use and risk of meningioma. Methods: Our study was a case-control study that involves 115 females, 40 cases who diagnosed with orbito-cranial meningioma and 75 controls of healthy, that has been presented in previous study. The demographic characteristics, reproductive factors, and history of progesterone use were obtained in-depth face-to-face interviews. PR and NF2 mRNA were assessed by real-time quantitative polymerase chain reaction (RT-qPCR) on serum specimens. Results: The mean age of participants in cases vs. controls were 46.6 ± 6.2 vs. 46.5 ± 7.45 (P = 0.969). The expression of PR and NF2 in cases was significantly lower than in controls. The longer duration of progesterone exposure was significantly associated with lower expression of PR and NF2. Significant association between lower expression of PR (OR 11.7; 95% CI 4.17-32.9; P < 0.001 comparing the lowest quartile vs. 3 highest quartile of PR) and NF2 (OR 4.23; 95% CI 1.85-9.67; P = 0.001 comparing the 2 lowest quartiles vs. 2 highest quartiles) with increased risk of meningioma were also reported. Conclusion: In this study we showed that the longer the exposure to exogenous progesterone, the lower the expression of PR and NF2 mRNA in the serum. Low expression of PR and NF2 were associated with higher risk of meningioma, suggesting that low PR expression and inactivation of NF2 might play a key role in progesterone-associated meningioma tumorigenesis and may be potential clinical marker for females at higher risk of meningioma.

Role of SIRPα in Homeostatic Regulation of T Cells and Fibroblastic Reticular Cells in the Spleen.

Signal regulatory protein α (SIRPα), is an immunoglobulin superfamily protein that is predominantly expressed in macrophages and dendritic cells (DCs), especially CD4+ conventional DCs (cDCs). In this study, we demonstrated that, in addition to the reduced number of CD4+ cDCs, the number of T cells was significantly decreased in the spleen of Sirpa-/- mice, in which full-length of SIRPα protein was systemically ablated. The size of the T cell zone was markedly reduced in the spleen of Sirpa-/- mice. In addition, Sirpa-/- mice revealed a marked reduction of CCL19, CCL21, and IL-7 expression, which are thought to be important for homeostasis of T cells in the spleen. Consistently, the abundance of fibroblastic reticular cells (FRCs), a subset of stromal cells in the T cell zone, was markedly reduced in the spleen of Sirpa-/- mice compared with Sirpaf/f mice. Moreover, we demonstrated that the mRNA expression of Lymphotoxin (LT) α, LTß, and LIGHT was significantly reduced in the spleen of Sirpa-/- mice. These data thus suggest that SIRPα is essential for steady-state homeostasis of T cells and FRCs in the spleen.