In Vivo Selection of Mycophenolate Mofetil-Resistant T Cells for Adoptive Immunotherapy.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3008-3008
Author(s):  
James Edward Griffin ◽  
Ben Carpenter ◽  
Emma Nicholson ◽  
Shao-an Xue ◽  
Martin Pule ◽  
...  
Keyword(s):  
T Cells ◽  
Mycophenolate Mofetil ◽  
Gene Transfer ◽  
Cd8 T Cells ◽  
Adoptive Immunotherapy ◽  
Selective Enrichment ◽  
In Vivo Selection ◽  
Selection Of

Abstract Abstract 3008 In vivo selection of mycophenolate mofetil-resistant T cells for adoptive immunotherapy. Background Following allogeneic solid organ or hematopoietic stem cell transplantation, adoptive transfer of therapeutic T cells may be hindered by the requirement for immune suppressive drugs to prevent rejection or graft-versus-host disease. Mycophenolate mofetil (MMF) is a non-competitive inhibitor of inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), an inducible enzyme that generate guanine nucleotides for DNA and RNA synthesis in T cells. In this study, we have evaluated the potential for gene transfer to T cells of a mutated IMPDH2 that confers >2000-fold resistance to MMF (IMPDH2R; T333I, S351Y). Methods Wild type IMPDH2WT, IMPDH2R and IMPDH2 with a catalytic site mutation (IMPDH2CS; C331A) were cloned into SFG retroviral vectors as fusions to eGFP reporter sequences. Murine thymoma (BW 5147) or CD8 T cells were transduced with each vector and their phenotype and function evaluated in the presence or absence of mycophenolic acid (MPA), the active metabolite of MMF. Results BW thymoma cells transduced with IMPDH2R exhibited less apoptosis than cells transduced with IMPDH2CS in response to MPA (ratio % Annexin V+ MPA: no MPA- IMPDH2R = 1.2; IMPDH2CS = 2.9, p=0.01). Cells transduced with IMPDH2R were also able to overcome the G1 cell-cycle arrest induced by MPA when compared to control IMPDH2CS cells (Ratio %cells in S-G2/M phases MPA: no MPA- IMPDH2R = 1.0; IMPDH2CS = 0.3, p=0.03). This led to selective enrichment of IMPDH2R transduced cells in the presence of MPA. At low dose MPA (450nM), IMPDH2R transduced cells enriched compared to IMPDH2CS but not IMPDH2WT (ratio % GFP MPA: no MPA- IMPDH2R = 1.6 vs IMPDH2CS = 1.1, p=0.04 and IMPDH2WT = 1.5 p= 0.14). However, at high dose (4500nM) IMPDH2R exhibited enhanced enrichment (ratio % GFP MPA: no MPA- IMPDH2R = 2.8 vs IMPDH2CS = 1.0 p=0.03 and vs IMPDH2WT= 1.5 p=0.03). Gene transfer of IMPDH2R into murine CD8 T cells also led to selective enrichment compared to controls in the presence of MPA when cultured with proliferation-inducing common gamma-chain cytokines (ratio MPA: no MPA IMPDH2R = 4.4 vs. IMPDH2CS = 1.10, p=0.02). Strong selection for IMPDH2R-tranduced CD8 OT-1 T cells in the presence of MPA was also observed under conditions of antigen-induced proliferation (ratio IMPDH2R= 7.1, control = 0.8, p=0.002). To assess in vivo selection, sub-lethally irradiated (2Gy) B6.PL (Thy1.1) mice were injected with a 1:1 mix of OT1 TCR transgenic Thy1.2 CD8 T cells transduced with IMPDH2R or IMPDH2CS that could be differentiated by the congenic markers CD45.1 and CD45.2. Transferred cells were stimulated by s.c. injection with cognate peptide (SIINFEKL) in IFA and MMF (200mg/kg/day) was given by daily ip injection. As in vitro, IMPDH2R-transduced OT1 cells were preferentially selected over IMPDH2CS-transduced cells following MMF treatment (day 14 ratio IMPDH2R to IMPDHCSwas 19.3 vs 1.2 in the absence of MMF). Conclusions T cells transduced with IMPDH2R are resistant to the anti-proliferative and apoptotic effects of MPA in vitro and demonstrate strong selection in vivo compared to controls at therapeutic levels of MMF. These data support the potential of conferring MMF resistance as a strategy to permit the survival of therapeutic T cells in immunosuppressed allograft recipients. Disclosures: Stauss: Cell Medica: Scientific Advisor Other.

Forced Expression of CC Chemokine Receptor 2 Enhances Anti-Cancer Reactivity Mediated by T Lymphocytes Beforehand Redirected Toward WT1 Inside the Tumor Microenvironment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2059-2059
Author(s):  
Hiroaki Asai ◽  
Hiroshi Fujiwara ◽  
Toshiki Ochi ◽  
Jun An ◽  
Toshiaki Shirakata ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Gene Transfer ◽  
Cell Line ◽  
Cd8 T Cells ◽  
Tcr Signaling ◽  
Ccr2 Gene ◽  
Anti Cancer

Abstract Abstract 2059 Background & Purpose: Redirected T-cell based adoptive therapy using cancer antigen-specific T-cell receptor (TCR) gene transfer has proven promise, however its clinical efficacy still remains unsatisfactory. The less accumulation in number of infused redirected T cells at the local tumor site is one of the causes. In order to accumulate those tumor-responsive T cells inside tumor microenvironment, chemokine produced by tumor cells and/or tumor associated cells is an attractive target. In this study, we examined the feasibility of CC chemokine receptor 2 (CCR2) gene transfer into T cells beforehand redirected toward WT1 in order to enhance the anti-cancer reactivity, both in vitro and in vivo. Methods: HLA-A*24:02-restricted and WT1235–243-specific TCR-a/b genes were introduced into normal CD8+ T cells using our novel retroviral TCR-gene expression vector encompassing silencers for endogenous TCRs (WT1-si-TCR vector). mRNA expression of total 11 chemokines expressed by 10 human lung cancer cell lines was examined using QRT-PCR, then CCL2 (variably produced in 7 out of 10 examined cell lines) and the small lung cancer cell line, LK79 which abundantly produced CCL2 was chosen for the proof of concept. Cloned CCR2 gene was retrovirally introduced into Jurkat cells, Jurkat/MA cells and normal CD8+ T cells similarly redirected beforehand using WT1-siTCR vector. Introduced CCR2 was validated using flow cytometer and transwell experiments. Cytotoxicity was examined using standard 51chromium release assay. Cooperative functionality composed of CCL2-directinality and WT1-specific antitumor cytotoxicity mediated by those double gene transfectants was examined in vitro; values of LDH released from destroyed LK79 cells in the bottom well by migrated double gene transduced CD8+ T cells from the upper well were measured. Antitumor reactivity in vivo was assessed using xenograft mouse model using luciferase-transduced LK79 cells (LK79-luc). Direct effect of CCL2 ligation on WT1-TCR signaling in double gene transfectant was assessed using luciferase assay with double gene transduced TCR− Jurkat/MA cell line, which stably expresses hCD8a and NFAT-luciferase reporter genes (Jurkat/MA/CD8a/luc; kindly provided by Prof. Erik Hooijberg, Netherlands). Results: CCL2 sensitivity was successfully introduced by CCR2 gene transfer; CCR2 transduced Jurkat successfully directed toward CCL2 producing cell line, LK79 cells. CCR2 gene transduction did not impede WT1-specific cytotoxicity mediated by CD8+ T cells beforehand redirected using WT1-siTCR gene transfer, rather double gene transduction cooperatively endowed those transfectants with CCL2 sensitivity and WT1-specific cytotoxicity against LK79 cells. Furthermore, in vivo assay using xenograft mouse model, growth of subcutaneously inoculated LK79-luc cells was more efficiently suppressed by those double gene transduced CD8+ T cells than WT1-siTCR single gene trnasfectants, in particular, immediately after adoptive transfer. Finally, CCL2 synergistically enhanced the magnitude of cognate peptide evoked WT1-specific TCR signaling in a dose dependent manner. Even without WT1 peptide ligation, such TCR signaling was similarly evoked by CCL2 to some extent. Conclusion: In this study, our results demonstrate that forced expression of CCR2 on CTL beforehand redirected toward WT1 enhanced its anti-cancer reactivity both in vitro and in vivo. This in vivo enhancement of antitumor reactivity may be caused by increased number of effector cells and enhanced WT1-TCR signaling generated both by CCL2 in the local tumor microenvironment. Although further studies are warranted, CCR2 gene transfer into redirected WT1-specific tumor-reactive CTL may be feasible for the treatment of human cancers. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

1994 ◽  
Vol 179 (4) ◽  
pp. 1273-1283 ◽  
Author(s):  
R Manetti ◽  
F Gerosa ◽  
M G Giudizi ◽  
R Biagiotti ◽  
P Parronchi ◽  
...  
Keyword(s):  
T Cells ◽  
Interferon Gamma ◽  
Specific Antigen ◽  
Th2 Cells ◽  
Interleukin 12 ◽  
T Helper ◽  
Ifn Gamma ◽  
Selection Of

Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.

scholarly journals CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells

2002 ◽  
Vol 197 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Melanie S. Vacchio ◽  
Richard J. Hodes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tolerance Induction ◽  
Peripheral Tolerance ◽  
Cd8 Cells ◽  
Costimulatory Signal ◽  
Cd28 Costimulation

Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y–specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y–specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals 708 Novel ways to exploit IL-21 to augment adoptive T cell transfer therapy against tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A737-A737
Author(s):  
Anna Cole ◽  
Guillermo Rangel RIvera ◽  
Aubrey Smith ◽  
Megan Wyatt ◽  
Brandon Ware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Striking Difference ◽  
T Cell Therapy ◽  
Cell Immunity ◽  
Emory University

BackgroundIL-21 enhances the anti-tumor capacity of adoptively transferred CD8+ T cells, while IL-2 and IL-15 impair T cell immunity by driving their expansion to a more differentiated status. Yet, these cytokines can act on many different immune cells. Given the potency of IL-21, we tested if this cytokine directly augments T cells or rather if it enhances other immune cells in the culture that indirectly improves T cell therapy.MethodsTo test this question, splenocytes from pmel-1 transgenic mice were used, as all CD8+ T cells express a transgenic TCR specific for tumor-antigen gp10025–33 overexpressed on melanoma. We then peptide activated naïve CD8+ T cells enriched or not from the spleen of pmel-1 mice and expanded them in the presence of IL-21 or IL-2 (10 ng/mL) for four days. Expanded pmel-1 from these various cultures were then restimulated with irradiated splenocytes pulsed with gp10025–33 and grown an additional seven days with IL-2 (10 ng/mL), irrespective of their initial cytokine condition. The in vitro memory phenotype, exhaustion profile, and cytokine secretion of these cultures were then assayed. Furthermore, mice bearing B16KVP melanoma tumors were infused with pmel-1 T cells expanded via these various approaches and compared for their relative capacity to engraft, persist, and regress tumor in vivo.ResultsInterestingly, we discovered that IL-21-treated T cells generated from bulk splenocytes are phenotypically and functionally distinct from IL-21-treated isolated T cells. Upon restimulation, IL-21-treated T cells from bulk splenocytes exhibited an exhausted phenotype that was like anergic IL-2-treated T cells. Moreover, few cells expressed CD62L but expressed heightened markers of suppression, including TIM3, PD-1, and EOMES. Moreover, they produced more effector molecules, including granzyme B and IFN-gamma. In vivo IL-21-treated T cells expanded from bulk splenocytes engrafted and persisted poorly, in turn mediating suboptimal regression of melanoma. Conversely, IL-21 dramatically bolstered the engraftment and antitumor activity of T cells only if they were first isolated from the spleen prior to their expansion and infusion into the animal.ConclusionsCollectively, our data shows that IL-21 may improve ACT therapy best when used directly on antitumor CD8+ T cells. Further studies will illuminate the mechanism behind this striking difference and determine whether other cell subsets reactive to IL-21 cause T cell dysfunction and/or reduced bioavailability. These findings are important for defining the best culture conditions in which to use IL-21 for ACT.AcknowledgementsWe would like to acknowledge Emory University, The Winship Cancer Institute, and the Pediatrics/Winship Flow Cytometry Core.Ethics ApprovalAll animal procedures were approved by the Institutional Animal Care and Use Committee of Emory University, protocol number 201900225.

scholarly journals The critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment

2020 ◽  
Author(s):  
Mohammad H. Rashid ◽  
Thaiz F. Borin ◽  
Roxan Ara ◽  
Raziye Piranlioglu ◽  
Bhagelu R. Achyut ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Cell Types ◽  
Biological Macromolecules

AbstractMyeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Our in vitro data suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. We confirmed the depletion of CD8 T-cells in vivo by treating the mice with MDSC exo. We also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. Our results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.

scholarly journals Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells

2018 ◽  
Vol 215 (9) ◽  
pp. 2265-2278 ◽  
Author(s):  
Colleen M. Lau ◽  
Ioanna Tiniakou ◽  
Oriana A. Perez ◽  
Margaret E. Kirkling ◽  
George S. Yap ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Cd8 T Cells ◽  
Functional Differentiation ◽  
Specific Gene ◽  
Hematopoietic Stem

An IRF8-dependent subset of conventional dendritic cells (cDCs), termed cDC1, effectively cross-primes CD8+ T cells and facilitates tumor-specific T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function and thrombopoiesis. We report that like HSPCs, cDCs express Etv6, but not its antagonist, ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow impaired the generation of cDC1-like cells in vitro and abolished the expression of signature marker CD8α on cDC1 in vivo. Moreover, Etv6-deficient primary cDC1 showed a partial reduction of cDC-specific and cDC1-specific gene expression and chromatin signatures and an aberrant up-regulation of pDC-specific signatures. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and the generation of tumor antigen–specific CD8+ T cells. Thus, Etv6 optimizes the resolution of cDC1 and pDC expression programs and the functional fitness of cDC1, thereby facilitating T cell cross-priming and tumor-specific responses.

scholarly journals STK3 Suppresses Ovarian Cancer Progression by Activating NF-κB Signaling to Recruit CD8+ T-Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Xiangyu Wang ◽  
Fengmian Wang ◽  
Zhi-Gang Zhang ◽  
Xiao-Mei Yang ◽  
Rong Zhang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Gene Set Enrichment Analysis ◽  
Ovarian Cancer Cells ◽  
And Migration

Serine/threonine protein kinase-3 (STK3) is a critical molecule of the Hippo pathway but little is known about its biological functions in the ovarian cancer development. We demonstrated the roles of STK3 in ovarian cancer. Existing databases were used to study the expression profile of STK3. STK3 was significantly downregulated in OC patients, and the low STK3 expression was correlated with a poor prognosis. In vitro cell proliferation, apoptosis, and migration assays, and in vivo subcutaneous xenograft tumor models were used to determine the roles of STK3. The overexpression of STK3 significantly inhibited cell proliferation, apoptosis, and migration of ovarian cancer cells in vitro and tumor growth in vivo. Bisulfite sequencing PCR analysis was performed to validate the methylation of STK3 in ovarian cancer. RNA sequencing and gene set enrichment analysis (GSEA) were used to compare the transcriptome changes in the STK3 overexpression ovarian cancer and control cells. The signaling pathway was analyzed by western blotting. STK3 promoted the migration of CD8+ T-cells by activating nuclear transcription factor κB (NF-κB) signaling. STK3 is a potential predictor of OC. It plays an important role in suppressing tumor growth of ovarian cancer and in chemotaxis of CD8+ T-cells.

scholarly journals Targeting JAK/STAT pathway in Takayasu’s arteritis

2020 ◽  
Vol 79 (7) ◽  
pp. 951-959 ◽  
Author(s):  
Paul Régnier ◽  
Alexandre Le Joncour ◽  
Anna Maciejewski-Duval ◽  
Anne-Claire Desbois ◽  
Cloé Comarmond ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Takayasu’S Arteritis ◽  
Signalling Pathway ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Takayasu's Arteritis

ObjectiveTakayasu’s arteritis (TAK) is a large vessel vasculitis with important infiltration of proinflammatory T cells in the aorta and its main branches, but its aetiology is still unknown. Our work aims to explore the involvement of Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signalling pathway in proinflammatory T cells differentiation and disease activity of TAK.MethodsWe analysed transcriptome and interferons gene signatures of fluorescence-activated cell sorting (FACS-sorted) CD4+ and CD8+ T cells from healthy donors (HD) and in 25 TAK (median age of 37.6 years including 21 active TAK with National Institutes of Health (NIH) score >1). Then we tested, in vitro and in vivo, the effects of JAK inhibitors (JAKinibs) in TAK.ResultsTranscriptome analysis showed 248 and 432 significantly dysregulated genes for CD4+ and CD8+ samples between HD and TAK, respectively. Among dysregulated genes, we highlighted a great enrichment for pathways linked to type I and type II interferons, JAK/STAT and cytokines/chemokines-related signalling in TAK. We confirmed by Real Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) the upregulation of type I interferons gene signature in TAK as compared with HD. JAKinibs induced both in vitro and in vivo a significant reduction of CD25 expression by CD4+ and CD8+ T cells, a significant decrease of type 1 helper T cells (Th1) and Th17 cells and an increase of Tregs cells in TAK. JAKinibs also decreased C reactive protein level, NIH score and corticosteroid dose in TAK patients.ConclusionsJAK/STAT signalling pathway is critical in the pathogenesis of TAK and JAKinibs may be a promising therapy.

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