Dendritic Cells Coordinate the Development and Homeostasis of Organ-Specific Regulatory T Cells

Leventhal, Daniel S.; Gilmore, Dana C.; Berger, Julian; Nishi, Saki; Lee, Victoria; Malchow, Sven; Kline, Douglas E.; Kline, Justin; Griend, Donald J. Vander; Huang, Haochu; Socci, Nicholas D.; Savage, Peter A.

doi:10.1016/j.immuni.2016.01.025

Cited by 88 publications

(101 citation statements)

References 47 publications

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“…Among these 72 candidate genes, genes that control cancer cell stemness (including NF-κB1 [34], IL-1β [35], and CCR7 [36, 37]) and that scored significantly in the screen were selected, thereby demonstrating the effectiveness of the screen. However, genes that control pluripotency (including IL-6, and STAT3 [38]) did not score significantly in the screen possibly reflecting insufficient knockdown, redundancy, or that their role in CSC identity did not involve OCT4 expression.…”

Section: Discussionmentioning

confidence: 99%

ICAM3 mediates inflammatory signaling to promote cancer cell stemness

et al. 2018

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In this study, we present a medium throughput siRNA screen platform to identify inflammation genes that regulate cancer cell stemness. We identified several novel candidates that decrease OCT4 expression and reduce the ALDH+ subpopulation both of which are characteristic of stemness. Furthermore, one of the novel candidates ICAM3 up-regulates in the ALDH+ subpopulation, the side population and the developed spheres. ICAM3 knockdown reduces the side population, sphere formation and chemo-resistance in MDA-MB-231 human breast cancer cells and A549 lung cancer cells. In addition, mice bearing MDA-MB-231-shICAM3 cells develop smaller tumors and fewer lung metastases versus control. Interestingly, ICAM3 recruits and binds to Src by the YLPL motif in its intracellular domain which further activates the PI3K-AKT phosphorylation cascades. The activated p-AKT enhances SOX2 and OCT4 activity and thereby maintains cancer cell stemness. Meanwhile, the p-AKT facilitated p50 nuclear translocation/activation enhances p50 feedback and thereby promotes ICAM3 expression by binding to the ICAM3 promoter region. On this basis, Src and PI3K inhibitors suppress ICAM3-mediated signaling pathways and reduce chemo-resistance which results in tumor growth suppression in vitro and in vivo. In summary, we identify a potential CSC regulator and suggest a novel mechanism by which ICAM3 governs cancer cell stemness and inflammation.

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Section: Discussionmentioning

confidence: 99%

ICAM3 mediates inflammatory signaling to promote cancer cell stemness

et al. 2018

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“…For selection to occur, developing thymocytes must interact with an array of thymic APCs (cTECs, mTECs, B cells, macrophages and DCs) that present thymically derived and peripherally transferred antigenic epitopes (3, 6, 7). In our study, we find that ectopic insulin (InsB 9–23 ) and agonist insulin (R22E) expression restricted to bone marrow derived APCs protect high and low affinity insulin specific TCR Rg mice from autoimmune diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that bone marrow derived APCs, including DCs, play a critical role in tTreg development by both AIRE-dependent and independent mechanisms (7). Foxp3 + tTreg development occurs in a restricted thymic niche regulated in part by the presence of APCs presenting cognate antigen (5, 51).…”

Section: Discussionmentioning

confidence: 99%

“…Medullary thymic epithelial cells can present a wide range of tissue restricted antigens (TRAs) driven by the endogenous expression of autoimmune regulator ( Aire ) (4, 5). Dendritic cells serve as a second self-antigen source by capturing and cross-presenting mTEC-derived TRAs or transporting tissue antigens from periphery to the thymus (6, 7). Why mechanisms of central tolerance can fail in autoimmune disorders, such as T1D, is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Ectopic Expression of Self-Antigen Drives Regulatory T Cell Development and Not Deletion of Autoimmune T Cells

Lee

Sprouse

Banerjee

et al. 2017

The Journal of Immunology

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Type 1 Diabetes (T1D) is a T cell-mediated autoimmune disease that is characterized by antigen specific targeting and destruction of insulin producing β cells. While multiple studies have characterized the pathogenic potential of β-cell specific T cells, we have limited mechanistic insight into self-reactive autoimmune T cell development and their escape from negative selection in the thymus. Here we demonstrate that ectopic expression of insulin B:9-23 (InsB9-23) by thymic antigen presenting cells is insufficient to induce deletion of high or low affinity InsB9-23 reactive CD4+ T cells; however, we observe an increase in the proportion and number of thymic and peripheral Foxp3+ regulatory cells T cells. In contrast, the MHC stable insulin mimetope (InsB9-23 R22E) efficiently deletes insulin specific T cells and prevents escape of high affinity thymocytes. Collectively, these results suggest that antigen dose and peptide:MHC complex stability can lead to multiple fates of insulin reactive CD4+ T cell development and autoimmune disease outcome.

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“…Self-antigens present in the thymus, either through Autoimmune Regulator (AIRE)-mediated tissue specific antigen expression or circulating Sirp1 + DCs, drive the development of tTregs [13][14][15][16][17]. Tregs can also develop in the periphery from mature CD4 + cells through non-inflammatory exposure to low-dose antigens.…”

Section: Tregs Are Critical Mediators Of Peripheral Tolerancementioning

confidence: 99%