miR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γc cytokines

Lymphodepleting regimens are used before adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic “cytokine sinks.” These conditioning modalities, however, are often associated with severe toxicities. We found that microRNA-155 (miR-155) enabled tumor-specific CD8+ T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T-cell responsiveness to limited amounts of homeostatic γc cytokines, resulting in delayed cellular contraction and sustained cytokine production. miR-155 restrained the expression of the inositol 5-phosphatase Ship1, an inhibitor of the serine-threonine protein kinase Akt, and multiple negative regulators of signal transducer and activator of transcription 5 (Stat5), including suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine phosphatase Ptpn2. Expression of constitutively active Stat5a recapitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumor-specific T cells can be used to increase the effectiveness of adoptive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers.

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A Role of Suppressor of Cytokine Signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated Interleukin 2 Production

Journal of Experimental Medicine ◽

10.1084/jem.20020939 ◽

2003 ◽

Vol 197 (4) ◽

pp. 425-436 ◽

Cited By ~ 59

Author(s):

Akira Matsumoto ◽

Yoh-ichi Seki ◽

Ryosuke Watanabe ◽

Katsuhiko Hayashi ◽

James A. Johnston ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Interleukin 2 ◽

Sh2 Domain ◽

Janus Kinase ◽

Expression Level ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Cd28 Costimulation

Suppressor of cytokine signaling (SOCS)3 has been characterized as a negative feedback regulator in cytokine-mediated Janus kinase signal transducer and activator of transcription signaling. However, this study shows that T cells from transgenic mice expressing SOCS3 exhibit a significant reduction in interleukin (IL)-2 production induced by T cell receptor cross-linking when T cells are costimulated with CD28. Decreased protein expression in SOCS3+/− mice enhanced CD28-mediated IL-2 production, clearly indicating the correlation between expression level of SOCS3 and IL-2 production ability. The SOCS3 protein interacted with phosphorylated CD28 through its SH2 domain but not the kinase inhibitory region. In addition, a point mutation in the SOCS3 SH2 domain attenuated the inhibition of CD28 function in IL-2 promoter activation. Committed T helper (Th)2 cells exclusively expressed SOCS3 and production of Th2 cytokines, such as IL-4 and IL-5, was much less dependent on CD28 costimulation compared with interferon γ and IL-2 production in Th1 cells. Consistent with this notion, the expression level of SOCS3 in early T cell activation influenced the ability of IL-2 production induced by CD28 costimulation. Therefore, the SOCS3 may play an alternative role in prohibiting excessive progression of CD28-mediated IL-2 production.

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Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation

Blood ◽

10.1182/blood-2004-08-3049 ◽

2005 ◽

Vol 106 (5) ◽

pp. 1668-1675 ◽

Cited By ~ 65

Author(s):

Mark M. W. Chong ◽

Donald Metcalf ◽

Emma Jamieson ◽

Warren S. Alexander ◽

Thomas W. H. Kay

Keyword(s):

T Cells ◽

T Cell ◽

Inflammatory Disease ◽

Lymphoid Cells ◽

Interleukin 12 ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Cytokine Network ◽

Activated T Cells ◽

Ifn Γ

Abstract The balance between pro- and anti-inflammatory cytokines modulates inflammation. Intracellular inhibitors of signaling, in turn, contribute to the negative regulation of cytokines. One of these inhibitors is suppressor of cytokine signaling-1 (SOCS-1). Socs1-/- mice die by 3 weeks of age with inflammation and fatty necrosis of the liver. Here, cre/loxP deletion of Socs1 was used to investigate the contribution of specific cells/tissues to inflammatory disease. Mice with SOCS-1 deficiency in myeloid and lymphoid cells, but not lymphoid alone, became ill at 50 to 250 days of age. These mice developed splenomegaly and T-cell/macrophage infiltration of many organs, including liver, lung, pancreas, and muscle. There were also abnormally high levels of the proinflammatory cytokines interferon γ (IFN-γ), tumor necrosis factor (TNF), and interleukin-12 (IL-12), and activated T cells circulating in these mice. Socs1null T cells were found to be hypersensitive to multiple cytokines, including IL-1, IL-2, and IL-12, resulting in IFN-γ production without requiring T-cell receptor (TCR) ligation. Additionally, Socs1null macrophages produced excessive amounts of IL-12 and TNF in response to other cytokines, including IFN-γ. A dysregulated cytokine network between T cells and macrophages is thus associated with this inflammatory disease. These findings indicate that SOCS-1 is critical in both T cells and macrophages for preventing uncontrolled inflammation. (Blood. 2005;106:1668-1675)

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Transcriptional Control of Impaired Th1 Responses in Patent Lymphatic Filariasis by T-Box Expressed in T Cells and Suppressor of Cytokine Signaling Genes

Infection and Immunity ◽

10.1128/iai.73.6.3394-3401.2005 ◽

2005 ◽

Vol 73 (6) ◽

pp. 3394-3401 ◽

Cited By ~ 23

Author(s):

Subash Babu ◽

V. Kumaraswami ◽

Thomas B. Nutman

Keyword(s):

T Cells ◽

Transcription Factor ◽

T Cell ◽

Mrna Expression ◽

Lymphatic Filariasis ◽

Th2 Cells ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

T Box ◽

Ifn Γ

ABSTRACT T-bet (T-box expressed in T cells) and GATA-3 are transcription factors that play a critical role in the development of Th1 and Th2 cells, as do genes of the SOCS (suppressor of cytokine signaling) family, albeit indirectly. Another transcription factor, Foxp3, is a master regulator of natural regulatory T cells (Tregs). To identify the role of these factors in impaired Th1 responses of patent filarial infection, analysis of cytokine, SOCS, and transcription factor mRNA expression was performed on purified T cells of filaria-infected individuals (n = 6) and uninfected controls (n = 6). As expected (and in contrast to cells of uninfected individuals), there was a significant depression of gamma interferon (IFN-γ) and a concomitant increase in interleukin-4 (IL-4), IL-5, and IL-10 mRNA expression following stimulation with parasite antigen (BmA) but not with a polyclonal T-cell (anti-CD3) stimulus. T-bet (but not GATA-3) was expressed at significantly lower levels in cells of filaria-infected individuals in response to BmA compared with those from the uninfected group, accounting, at least partially, for the diminished IFN-γ expression. Second, we found no significant differences in expression of Foxp3 between the two groups, although induction of Foxp3 expression correlated with induced expression levels of IL-10, implicating Tregs in the IL-10 expression seen. Finally, parasite-specific T-cell expression of SOCS-1, SOCS-5, and SOCS-7 was significantly diminished among infected patients; in contrast, expression of SOCS-3 increased. Our data therefore indicate that the impaired Th1 responses observed in patent lymphatic filariasis are associated with decreased expression of T-bet, SOCS-1, SOCS-5, and SOCS-7 and increased expression of SOCS-3 in T cells.

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Suppressor of cytokine signaling 3 regulates CD8 T-cell proliferation by inhibition of interleukins 6 and 27

Blood ◽

10.1182/blood-2006-08-041541 ◽

2007 ◽

Vol 110 (7) ◽

pp. 2528-2536 ◽

Cited By ~ 39

Author(s):

Christine Brender ◽

Gillian M. Tannahill ◽

Brendan J. Jenkins ◽

Joel Fletcher ◽

Ruth Columbus ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Signaling Pathways ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Cell Receptor ◽

Striking Similarity ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling

Suppressor of cytokine signaling (SOCS) proteins regulate the intensity and duration of cytokine responses. SOCS3 is expressed in peripheral T cells, and recent reports have suggested that overexpression of SOCS3 modulates antigen- and/or costimulation-induced T-cell activation. To study the role of SOCS3 in the regulation of T-cell activation, we used a conditional gene-targeting strategy to generate mice that lack SOCS3 in T/natural killer T cells (Socs3ΔLck/ΔLck mice). SOCS3-deficient CD8 T cells showed greater proliferation than wild-type cells in response to T-cell receptor (TCR) ligation despite normal activation of signaling pathways downstream from TCR or CD28 receptors. Signaling in response to the gp130 cytokines interleukin (IL)–6 and IL-27 was prolonged in Socs3ΔLck/ΔLck T cells, and T cells from gp130Y757F/Y757F mice, in which the SOCS3-binding site on gp130 is ablated, showed a striking similarity to SOCS3-deficient CD8 T cells. Although the proliferative defect of Socs3ΔLck/ΔLck T cells was not rescued in the absence of IL-6, suppression of IL-27 signaling was found to substantially reduce anti-CD3–induced proliferation. We conclude that enhanced responses to TCR ligation by SOCS3-deficient CD8 T cells are not caused by aberrant TCR-signaling pathways but, rather, that increased IL-27 signaling drives unregulated proliferation in the absence of SOCS3.

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THEMIS is a priming substrate of non-receptor tyrosine phosphatase PTPN6/SHP1 and plays dual roles during T cell development

10.1101/2021.12.21.473566 ◽

2021 ◽

Author(s):

Jiali Zhang ◽

Erwei Zuo ◽

Minfang Song ◽

Li Chen ◽

Zhenzhou Jiang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Tyrosine Phosphatase ◽

Cytokine Signaling ◽

Tcr Signaling ◽

Dual Roles ◽

Thymic Development ◽

Tcr Activation ◽

Receptor Tyrosine Phosphatase

THEMIS plays an indispensable role in T cells, but its mechanism of action is highly controversial. Using the systematic proximity labeling methodology PEPSI, we identified THEMIS as an uncharacterized substrate for the phosphatase SHP1. Saturated mutagenesis analysis revealed that THEMIS phosphorylation at the evolutionally conserved Tyr34 residue was oppositely regulated by SHP1 and the kinase LCK. Like THEMIS-/- mice, THEMIS Y34F/Y34F knock-in mice showed a significant decrease in CD4 thymocytes and mature CD4 T cells, but a normal thymic development and peripheral homeostasis of CD8 T cells. Mechanistically, phosphorylated THEMIS induced by TCR activation acts as a "priming substrate" to bind SHP1 and convert its phosphatase activity from basal level to nearly fully activated level, ensuring an appropriate negative regulation of TCR signaling. However, cytokine signaling in CD8 T cells failed to elicit THEMIS Y34 phosphorylation, revealing both phosphorylation-dependent and -independent roles of THEMIS in controlling T cell maturation and expansion.

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Engineering Next-Generation CAR-T Cells for Better Toxicity Management

International Journal of Molecular Sciences ◽

10.3390/ijms21228620 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8620

Author(s):

Alain E. Andrea ◽

Andrada Chiron ◽

Stéphanie Bessoles ◽

Salima Hacein-Bey-Abina

Keyword(s):

T Cells ◽

T Cell ◽

Antigen Receptors ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Safety Strategies ◽

Life Threatening ◽

Preclinical And Clinical Studies

Immunoadoptive therapy with genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) has revolutionized the treatment of patients with hematologic cancers. Although clinical outcomes in B-cell malignancies are impressive, researchers are seeking to enhance the activity, persistence, and also safety of CAR-T cell therapy—notably with a view to mitigating potentially serious or even life-threatening adverse events like on-target/off-tumor toxicity and (in particular) cytokine release syndrome. A variety of safety strategies have been developed by replacing or adding various components (such as OFF- and ON-switch CARs) or by combining multi-antigen-targeting OR-, AND- and NOT-gate CAR-T cells. This research has laid the foundations for a whole new generation of therapeutic CAR-T cells. Here, we review the most promising CAR-T cell safety strategies and the corresponding preclinical and clinical studies.

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Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X

Journal of Experimental Medicine ◽

10.1084/jem.20140860 ◽

2014 ◽

Vol 211 (10) ◽

pp. 1947-1955 ◽

Cited By ~ 35

Author(s):

Edwina Naik ◽

Joshua D. Webster ◽

Jason DeVoss ◽

Jinfeng Liu ◽

Rowena Suriben ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tolerance Induction ◽

Ubiquitin Ligases ◽

Cell Receptor ◽

Lymphoproliferative Disease ◽

Deubiquitinating Enzymes ◽

Tcr Signaling ◽

Self Tolerance ◽

A Cell

The T cell hyperproliferation and autoimmune phenotypes that manifest in mice lacking E3 ubiquitin ligases such as Cbl, ITCH, or GRAIL highlight the importance of ubiquitination for the maintenance of peripheral T cell tolerance. Less is known, however, about the deubiquitinating enzymes that regulate T cell proliferation and effector function. Here, we define a cell intrinsic role for the deubiquitinase Usp9X during proximal TCR signaling. Usp9X-deficient T cells were hypoproliferative, yet mice with T cell–specific Usp9x deletion had elevated numbers of antigen-experienced T cells and expanded PD-1 and OX40-expressing populations consistent with immune hyperactivity. Aged Usp9x KO mice developed lupus-like autoimmunity and lymphoproliferative disease, indicating that ubiquitin ligases and deubiquitinases maintain the delicate balance between effective immunity and self-tolerance.

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Heat Shock Protein 60 Activates Cytokine-Associated Negative Regulator Suppressor of Cytokine Signaling 3 in T Cells: Effects on Signaling, Chemotaxis, and Inflammation

The Journal of Immunology ◽

10.4049/jimmunol.175.1.276 ◽

2005 ◽

Vol 175 (1) ◽

pp. 276-285 ◽

Cited By ~ 52

Author(s):

Alexandra Zanin-Zhorov ◽

Guy Tal ◽

Shoham Shivtiel ◽

Michal Cohen ◽

Tsvee Lapidot ◽

...

Keyword(s):

T Cells ◽

Heat Shock ◽

Heat Shock Protein ◽

Negative Regulator ◽

Cytokine Signaling ◽

Heat Shock Protein 60 ◽

Suppressor Of Cytokine Signaling

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Abstract 129: Suppressor of Cytokine Signaling 1 in Dendritic Cells Inhibits Myocardial Inflammation in Experimental Autoimmune Myocarditis

Circulation Research ◽

10.1161/res.111.suppl_1.a129 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Kazuko Tajiri ◽

Kyoko Imanaka-Yoshida ◽

Michiaki Hiroe ◽

Nobutake Shimojo ◽

Satoshi Sakai ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cytokine Signaling ◽

Autoimmune Myocarditis ◽

Dc Function ◽

Autoreactive T Cell ◽

Experimental Autoimmune Myocarditis ◽

Experimental Autoimmune

Introduction: Autoimmunity is considered to play an important role in the development of myocarditis and dilated cardiomyopathy. Recent reports have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies. Suppressor of cytokine signaling1 (SOCS1) is an intracellular, cytokine-inducible protein that regulates the responses of immune cells to cytokines. We therefore hypothesized that overexpression of SOCS1 may inhibit the inflammation of myocarditis and cardiomyopathy. Methods and Results: Myocarditis was induced by subcutaneous immunization with cardiac specific peptides derived from α-myosin heavy chain in BALB/c mice on days 0 and 7. Plasmid DNA encoding SOCS1 (pSOCS1) was injected intraperitoneally into mice on days 0, 5 and 10. pSOCS1 treatment significantly decreased heart-to-body weight ratios and the number of infiltrating cells in the heart. Echocardiography showed preserved contractile function in pSOCS1-treated mice. Although autoimmune myocarditis is a CD4+ T cell-mediated disease, pSOCS1 treatment does not have a direct suppressive effect on autoreactive T-cell activation. The introduced pSOCS1 suppressed proinflammatory cytokine production and STAT1 phosphorylation in dendritic cells (DCs). In addition, the proliferative responses of autoreactive CD4+ T cells co-cultured with DCs from pSOCS1-treated mice were much weaker than those of cells cultured with DCs from control plasmid-injected mice. These results suggested that the inoculated pSOCS1 may have been transfected into DCs and impaired DC function in vivo. Conclusion: The administration of pSOCS1 protected mice from the development of experimental autoimmune myocarditis, which was mediated by the inhibition of DC function that in turn reduced the activation of autoreactive CD4+ T cells.

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