scholarly journals IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells

Blood ◽  
2012 ◽  
Vol 120 (17) ◽  
pp. 3478-3487 ◽  
Author(s):  
Solenne Vigne ◽  
Gaby Palmer ◽  
Praxedis Martin ◽  
Céline Lamacchia ◽  
Deborah Strebel ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Interleukin 1 ◽  
Th1 Cell ◽  
Critical Function ◽  
Mediators Of Inflammation ◽  
Th1 Polarization

AbstractThe interleukin-1 (IL-1) superfamily of cytokines comprises a set of pivotal mediators of inflammation. Among them, the action of IL-36 cytokines in immune responses has remained elusive. In a recent study, we demonstrated a direct effect of IL-36 on immune cells. Here we show that, among T cells, the IL-36 receptor is predominantly expressed on naive CD4+ T cells and that IL-36 cytokines act directly on naive T cells by enhancing both cell proliferation and IL-2 secretion. IL-36β acts in synergy with IL-12 to promote Th1 polarization and IL-36 signaling is also involved in mediating Th1 immune responses to Bacillus Calmette-Guerin infection in vivo. Our findings point toward a critical function of IL-36 in the priming of Th1 cell responses in vitro, and in adaptive immunity in a model of mycobacterial infection in vivo.

scholarly journals In Vivo Priming of Cd4 T Cells That Produce Interleukin (Il)-2 but Not IL-4 or Interferon (Ifn)-γ, and Can Subsequently Differentiate into IL-4–Or IFN-γ–Secreting Cells

2001 ◽  
Vol 194 (8) ◽  
pp. 1069-1080 ◽  
Author(s):  
Xiaowen Wang ◽  
Tim Mosmann
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Effector Cells ◽  
Ifn Γ

The differentiation of antigen-stimulated naive CD4 T cells into T helper (Th)1 or Th2 effector cells can be prevented in vitro by transforming growth factor (TGF)-β and anti–interferon (IFN)-γ. These cells proliferate and synthesize interleukin (IL)-2 but not IFN-γ or IL-4, and can differentiate into either Th1 or Th2 cells. We have now used two-color Elispots to reveal substantial numbers of primed cells producing IL-2 but not IL-4 or IFN-γ during the Th1- or Th2-biased immune responses induced by soluble proteins or with adjuvants. These cells were CD4+CD44high and were present during immediate and long-term immune responses of normal mice. Naive T cell receptor for antigen (TCR) transgenic (DO11.10) T cells were primed in vivo after adoptive transfer into normal hosts and FACS® cloned under conditions that did not allow further differentiation. After clonal proliferation, aliquots of each clone were cultured in Th1- or Th2-inducing conditions. Many in vivo–primed cells were uncommitted, secreting IL-2 but not IL-4 or IFN-γ at the first cloning step, but secreting either IL-4 or IFN-γ after differentiation in the appropriate conditions. These in vivo-primed, uncommitted, IL-2–producing cells may constitute an expanded pool of antigen-specific cells that provide extra flexibility for immune responses by differentiating into Th1 or Th2 phenotypes later during the same or subsequent immune responses.

scholarly journals CD4+ T Cells in Lymph Nodes of UVB-Irradiated Mice Suppress Immune Responses to New Antigens Both In Vitro and In Vivo

2007 ◽  
Vol 127 (4) ◽  
pp. 915-924 ◽  
Author(s):  
Shelley Gorman ◽  
Jamie W.-Y. Tan ◽  
Stephanie T. Yerkovich ◽  
John J. Finlay-Jones ◽  
Prue H. Hart
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Cd4 T Cells

CD137 Identifies a Population of Regulatory T Cells That Inhibit Anti-Tumor Immune Responses In Adoptive Immunotherapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2093-2093
Author(s):  
Matthew J Goldstein ◽  
Holbrook E Kohrt ◽  
Roch Houot ◽  
Bindu Varghese ◽  
Jack T Lin ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Adoptive Immunotherapy ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Surface Markers ◽  
Cd4 Cells ◽  
Treg Population

Abstract Abstract 2093 Background: Adoptive immunotherapy is a promising novel approach to the treatment of cancer. However, clinical translation of adoptively transferred CD4 T cells is limited by cotransfer of an inhibitory population of regulatory CD4 T cells (Tregs). We identified a method of isolating viable antitumor CD4 T cells while excluding Tregs based on two surface markers—CD44 and CD137. Methods: We have developed a model for adoptive cell therapy of lymphoma whereby anti-tumor T cells are generated in vivo through vaccination with a CpG-loaded whole cell vaccine (CpG/H11). These vaccine-induced cells can protect from lethal tumor challenge when isolated and transferred into lethally irradiated, syngeneic recipient mice. We investigated the subsets of T cells involved in the anti-tumor response through a combination of in vitro and in vivo assays. Results: Adoptive transfer of CD137negCD44hi CD4 T cells, but not other sub-populations, provided protection from B cell lymphoma. We demonstrate that the population of CD137posCD44hi CD4 T cells consists primarily of activated Tregs. In vitro, these CD137pos cells suppressed the proliferation of effector cells in a contact-dependent manner. We observed that this CD137pos Treg population persisted following adoptive transfer and maintained expression of FoxP3 as well as CD137. Moreover, the addition of CD137posCD44hi CD4 cells to CD137negCD44hi CD4 cells suppressed the antitumor immune response. In the presence of CD137posCD44hi CD4 T cells, homing of other T cell populations to tumor sites was disrupted. These results suggest that CD137 expression on CD4 T cells defines a population of activated Tregs that prevent antitumor immune responses. Conclusions: Our findings identify two surface markers that can be used to facilitate the enrichment of anti-tumor CD4 T cells while depleting an inhibitory Treg population. This approach has direct applicability to clinical trials for patients with lymphoma. Disclosures: No relevant conflicts of interest to declare.

Comparison of In Vitro and In Vivo Effects of Infliximab on Cytokine Production in Proliferating CD4+ T Cells in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 1 (2) ◽  
pp. 122-128
Author(s):  
Syuichi Koarada ◽  
Yuri Sadanaga ◽  
Natsumi Nagao ◽  
Satoko Tashiro ◽  
Rie Suematsu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production

scholarly journals Reovirus-induced cell-mediated immunity for the treatment of multiple myeloma within the resistant bone marrow niche

2021 ◽  
Vol 9 (3) ◽  
pp. e001803
Author(s):  
Louise M E Müller ◽  
Gemma Migneco ◽  
Gina B Scott ◽  
Jenny Down ◽  
Sancha King ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Immune Responses ◽  
Stromal Cells ◽  
Tumor Burden ◽  
Effector Memory ◽  
In Vivo Model ◽  
Bm Niche

BackgroundMultiple myeloma (MM) remains an incurable disease and oncolytic viruses offer a well-tolerated addition to the therapeutic arsenal. Oncolytic reovirus has progressed to phase I clinical trials and its direct lytic potential has been extensively studied. However, to date, the role for reovirus-induced immunotherapy against MM, and the impact of the bone marrow (BM) niche, have not been reported.MethodsThis study used human peripheral blood mononuclear cells from healthy donors and in vitro co-culture of MM cells and BM stromal cells to recapitulate the resistant BM niche. Additionally, the 5TGM1-Kalw/RijHSD immunocompetent in vivo model was used to examine reovirus efficacy and characterize reovirus-induced immune responses in the BM and spleen following intravenous administration. Collectively, these in vitro and in vivo models were used to characterize the development of innate and adaptive antimyeloma immunity following reovirus treatment.ResultsUsing the 5TGM1-Kalw/RijHSD immunocompetent in vivo model we have demonstrated that reovirus reduces both MM tumor burden and myeloma-induced bone disease. Furthermore, detailed immune characterization revealed that reovirus: (i) increased natural killer (NK) cell and CD8+ T cell numbers; (ii) activated NK cells and CD8+ T cells and (iii) upregulated effector-memory CD8+ T cells. Moreover, increased effector-memory CD8+ T cells correlated with decreased tumor burden. Next, we explored the potential for reovirus-induced immunotherapy using human co-culture models to mimic the myeloma-supportive BM niche. MM cells co-cultured with BM stromal cells displayed resistance to reovirus-induced oncolysis and bystander cytokine-killing but remained susceptible to killing by reovirus-activated NK cells and MM-specific cytotoxic T lymphocytes.ConclusionThese data highlight the importance of reovirus-induced immunotherapy for targeting MM cells within the BM niche and suggest that combination with agents which boost antitumor immune responses should be a priority.

scholarly journals Selective elimination of immunosuppressive T cells in patients with multiple myeloma

Leukemia ◽  
2021 ◽  
Author(s):  
Mohamed H. S. Awwad ◽  
Abdelrahman Mahmoud ◽  
Heiko Bruns ◽  
Hakim Echchannaoui ◽  
Katharina Kriegsmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Immune Responses ◽  
High Frequency ◽  
Surface Markers ◽  
Selective Elimination ◽  
Related Transcription Factor ◽  
Cell Membrane Protein

AbstractElimination of suppressive T cells may enable and enhance cancer immunotherapy. Here, we demonstrate that the cell membrane protein SLAMF7 was highly expressed on immunosuppressive CD8+CD28-CD57+ Tregs in multiple myeloma (MM). SLAMF7 expression associated with T cell exhaustion surface markers and exhaustion-related transcription factor signatures. T cells from patients with a high frequency of SLAMF7+CD8+ T cells exhibited decreased immunoreactivity towards the MART-1aa26–35*A27L antigen. A monoclonal anti-SLAMF7 antibody (elotuzumab) specifically depleted SLAMF7+CD8+ T cells in vitro and in vivo via macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Anti-SLAMF7 treatment of MM patients depleted suppressive T cells in peripheral blood. These data highlight SLAMF7 as a marker for suppressive CD8+ Treg and suggest that anti-SLAMF7 antibodies can be used to boost anti-tumoral immune responses in cancer patients.

scholarly journals Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes

2000 ◽  
Vol 191 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Zhengbin Lu ◽  
Lingxian Yuan ◽  
Xianzheng Zhou ◽  
Eduardo Sotomayor ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Communication ◽  
Cd8 T Cell ◽  
Cd4 Help ◽  
T Cell Help

In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.

scholarly journals Human Effector Memory CD4+ T Cells Directly Recognize Allogeneic Endothelial Cells In Vitro and In Vivo

2007 ◽  
Vol 179 (7) ◽  
pp. 4397-4404 ◽  
Author(s):  
Stephen L. Shiao ◽  
Nancy C. Kirkiles-Smith ◽  
Benjamin R. Shepherd ◽  
Jennifer M. McNiff ◽  
Edward J. Carr ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cd4 T Cells ◽  
Effector Memory ◽  
Memory Cd4 T Cells

scholarly journals Differential Activation of CD8+Tumor-Specific Tc1 and Tc2 Cells by an IL-10-Producing Murine Plasmacytoma

1998 ◽  
Vol 6 (3-4) ◽  
pp. 331-342 ◽  
Author(s):  
Christoph Specht ◽  
Hans-Gerd Pauels ◽  
Christian Becker ◽  
Eckehart Kölsch
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Tumor Cells ◽  
T Cell Subsets ◽  
Early Stages ◽  
Specific Tolerance

The involvement of counteractiveCD8+T-cell subsets during tumor-specific immune responses was analyzed in a syngeneic murine plasmacytoma model.CD8+Tc cells against the immunogenic IL-10-producing BALB/c plasmacytoma ADJ-PC-5 can be easily induced by immunization of BALB/c mice with X-irradiated ADJ-PC-5 tumor cellsin vivoandin vitro. However, the failure of recipient mice to mount a protective Tc response against the tumor during early stages of a real or simulated tumor growth is not due to immunological ignorance, but depends on the induction of tumor-specific tolerance, involving a population of tumorinducedCD8+T cells that are able to inhibit the generation of tumor-specific Tc cells in a primary ADJ-PC-5-specific MLTC, using IFN-γas a suppressive factor. Whereas most longterm cultivated CD8+ADJ-PC-5-specific Tc lines produce type-1 cytokines on stimulation, at least two of them, which were derived from a primary MLTC, display a type-2 cytokine spectrum. Furthermore, the primaryin vitroTc response against ADJ-PC-5 cells shows characteristics of a Tc2 response. The Tc response is strictly depending on tumor-derived IL-10.CD8+Tc cells that are induced in a primary MLTC do not produce IFN-γ, and the tumor-specific Tc response is enhanced by IL-4 but suppressed by IFN-γor IL-12. In contrast, ADJ-PC- 5-specificCD8+Tc cells from immunized mice are IFN-γproducing Tc1 cells. Since the primaryin vitroTc response against the tumor is suppressed even by the smallest numbers of irradiated ADJ-PC-5-specific Tc1 cells via IFN-γthese Tc1 cells behave similar to the suppressiveCD8+T cells that are induced during early stages of ADJ-PC-5 tumorigenesis.

scholarly journals Peyer's Patch Dendritic Cells Process Viral Antigen from Apoptotic Epithelial Cells in the Intestine of Reovirus-infected Mice

2004 ◽  
Vol 200 (2) ◽  
pp. 235-245 ◽  
Author(s):  
Marina N. Fleeton ◽  
Nikhat Contractor ◽  
Francisco Leon ◽  
J. Denise Wetzel ◽  
Terence S. Dermody ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Cd4 T Cells ◽  
Cell Protein ◽  
Peyer’S Patch ◽  
Peyer's Patch ◽  
Antigen Uptake ◽  
Cross Presentation

We explored the role of Peyer's patch (PP) dendritic cell (DC) populations in the induction of immune responses to reovirus strain type 1 Lang (T1L). Immunofluorescence staining revealed the presence of T1L structural (σ1) and nonstructural (σNS) proteins in PPs of T1L-infected mice. Cells in the follicle-associated epithelium contained both σ1 and σNS, indicating productive viral replication. In contrast, σ1, but not σNS, was detected in the subepithelial dome (SED) in association with CD11c+/CD8α−/CD11blo DCs, suggesting antigen uptake by these DCs in the absence of infection. Consistent with this possibility, PP DCs purified from infected mice contained σ1, but not σNS, and PP DCs from uninfected mice could not be productively infected in vitro. Furthermore, σ1 protein in the SED was associated with fragmented DNA by terminal deoxy-UTP nick-end labeling staining, activated caspase-3, and the epithelial cell protein cytokeratin, suggesting that DCs capture T1L antigen from infected apoptotic epithelial cells. Finally, PP DCs from infected mice activated T1L-primed CD4+ T cells in vitro. These studies show that CD8α−/CD11blo DCs in the PP SED process T1L antigen from infected apoptotic epithelial cells for presentation to CD4+ T cells, and therefore demonstrate the cross-presentation of virally infected cells by DCs in vivo during a natural viral infection.

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