RESUMO
Effective immunity requires a large, diverse naive T cell repertoire circulating among lymphoid organs in search of antigen. Sphingosine 1-phosphate (S1P) and its receptor S1PR1 contribute by both directing T cell migration and supporting T cell survival. Here, we addressed how S1P enables T cell survival and the implications for patients treated with S1PR1 antagonists. We found that S1PR1 limited apoptosis by maintaining the appropriate balance of BCL2 family members via restraint of JNK activity. Interestingly, the same residues of S1PR1 that enable receptor internalization were required to prevent this proapoptotic cascade. Findings in mice were recapitulated in ulcerative colitis patients treated with the S1PR1 antagonist ozanimod, and the loss of naive T cells limited B cell responses. Our findings highlighted an effect of S1PR1 antagonists on the ability to mount immune responses within lymph nodes, beyond their effect on lymph node egress, and suggested both limitations and additional uses of this important class of drugs.
Assuntos
Linfonodos , Linfócitos T , Animais , Humanos , Camundongos , Linfócitos B , Linfonodos/patologia , Lisofosfolipídeos , Receptores de Lisoesfingolipídeo/genética , Transdução de Sinais , Esfingosina , Receptores de Esfingosina-1-FosfatoRESUMO
Plasma cells (PCs) are essential for humoral immunity, as they are responsible for the production of antibodies and contribute to immunological memory. Despite their importance, differentiating between long-lived and short-lived PCs in vivo remains a challenge due to a lack of specific markers to distinguish these populations. Addressing this gap, our study introduces a novel J-chain CreERT2 GFP allele (IgJCreERT2) for precise genetic studies of PCs. This model takes advantage of PC-restricted expression of the J-chain gene, enabling temporal and cell-specific tracking of PCs utilizing a tamoxifen-inducible Cre recombinase. Our in vitro and in vivo validation studies of the inducible Cre allele confirmed the fidelity and utility of this model and demonstrated the model's ability to trace the long-lived PC population in vivo following immunization. The IgJCreERT2 model allowed for detailed analysis of surface marker expression on PCs, revealing insights into PC heterogeneity and characteristics. Our findings not only validate the IgJCreERT2 mouse as a reliable tool for studying PCs but also facilitate the investigation of PC dynamics and longevity, particularly in the context of humoral immunity and vaccine responses. This model represents a significant advancement for the in-depth study of PCs in health and disease, offering a new avenue for the exploration of PC biology and immunological memory.
RESUMO
Effective immunity requires a large, diverse naïve T cell repertoire circulating among lymphoid organs in search of antigen. Sphingosine 1-phosphate (S1P) and its receptor S1PR1 contribute by both directing T cell migration and supporting T cell survival. Here, we address how S1P enables T cell survival, and the implications for patients treated with S1PR1 antagonists. Contrary to expectations, we found that S1PR1 limits apoptosis by maintaining the appropriate balance of BCL2 family members via restraint of JNK activity. Interestingly, the same residues of S1PR1 that enable receptor internalization are required to prevent this pro-apoptotic cascade. Findings in mice were recapitulated in ulcerative colitis patients treated with the S1PR1 antagonist ozanimod, and the loss of naïve T cells limited B cell responses. Our findings highlight an unexpected effect of S1PR1 antagonists on the ability to mount immune responses within lymph nodes, beyond their effect on lymph node egress, and suggest both limitations and novel uses of this important class of drugs.
RESUMO
During an immune response, the duration of T cell residence in lymphoid and non-lymphoid tissues likely affects T cell activation, differentiation, and memory development. The factors that govern T cell transit through inflamed tissues remain incompletely understood, but one important determinant of T cell exit from tissues is sphingosine 1-phosphate (S1P) signaling. In homeostasis, S1P levels are high in blood and lymph compared to lymphoid organs, and lymphocytes follow S1P gradients out of tissues into circulation using varying combinations of five G-protein coupled S1P receptors. During an immune response, both the shape of S1P gradients and the expression of S1P receptors are dynamically regulated. Here we review what is known, and key questions that remain unanswered, about how S1P signaling is regulated in inflammation and in turn how S1P shapes immune responses.
Assuntos
Receptores de Lisoesfingolipídeo , Linfócitos T , Humanos , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais , Ativação LinfocitáriaRESUMO
In this elegant study, Evrard et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210116) find that sphingosine 1-phosphate receptor 5 (S1PR5) powerfully impairs tissue-resident memory T cell (TRM) formation, and that tissue-derived TGF-ß limits S1pr5 expression by infiltrating T cells.
Assuntos
Células T de Memória , Receptores de Esfingosina-1-FosfatoRESUMO
Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B1 (AFB1), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an "eicosanoid and cytokine storm." AFB1-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including BiP, CHOP, and PDI in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cytokine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.
Assuntos
Citocinas/metabolismo , Eicosanoides/metabolismo , Neoplasias Hepáticas/metabolismo , Aflatoxina B1/efeitos adversos , Animais , Apoptose , Carcinogênese/metabolismo , Carcinógenos/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Citocinas/imunologia , Progressão da Doença , Eicosanoides/imunologia , Epóxido Hidrolases/metabolismo , Células Hep G2 , Humanos , Inflamação/metabolismo , Neoplasias Hepáticas/fisiopatologia , Macrófagos/metabolismo , Camundongos , Processos NeoplásicosRESUMO
Sulforaphane (SFN) is a compound [1-isothiocyanato-4-(methylsulfinyl)-butane] found in broccoli and other cruciferous vegetables that is currently of interest because of its potential as a chemopreventive and a chemotherapeutic drug. Recent studies in a diverse range of cellular and animal models have shown that SFN is involved in multiple intracellular pathways that regulate xenobiotic metabolism, inflammation, cell death, cell cycle progression, and epigenetic regulation. In order to better understand the mechanisms of action behind SFN-induced cell death, we undertook an unbiased genome wide screen with the yeast knockout (YKO) library to identify SFN sensitive (SFNS) mutants. The mutants were enriched with knockouts in genes linked to vacuolar function suggesting a link between this organelle and SFN's mechanism of action in yeast. Our subsequent work revealed that SFN increases the vacuolar pH of yeast cells and that varying the vacuolar pH can alter the sensitivity of yeast cells to the drug. In fact, several mutations that lower the vacuolar pH in yeast actually made the cells resistant to SFN (SFNR). Finally, we show that human lung cancer cells with more acidic compartments are also SFNR suggesting that SFN's mechanism of action identified in yeast may carry over to higher eukaryotic cells.