scholarly journals Safety and immunologic effects of IL-15 administration in nonhuman primates

Blood ◽  
2009 ◽  
Vol 114 (12) ◽  
pp. 2417-2426 ◽  
Author(s):  
Carolina Berger ◽  
Michael Berger ◽  
Robert C. Hackman ◽  
Michael Gough ◽  
Carole Elliott ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Nonhuman Primates ◽  
Interleukin 2 ◽  
Limited Data ◽  
Intermittent Administration ◽  
Cell Immunity ◽  
Cd8 T Cell Memory ◽  
Cd8 Memory T Cells

Abstract The administration of cytokines that modulate endogenous or transferred T-cell immunity could improve current approaches to clinical immunotherapy. Interleukin-2 (IL-2) is used most commonly for this purpose, but causes systemic toxicity and preferentially drives the expansion of CD4+CD25+Foxp3+ regulatory T cells, which can inhibit antitumor immunity. IL-15 belongs to the γc cytokine family and possesses similar properties to IL-2, including the ability to induce T-cell proliferation. Whereas IL-2 promotes apoptosis and limits the survival of CD8+ memory T cells, IL-15 is required for the establishment and maintenance of CD8+ T-cell memory. However, limited data are available to guide the clinical use of IL-15. Here, we demonstrate in nonhuman primates that IL-15 administration expands memory CD8+ and CD4+ T cells, and natural killer (NK) cells in the peripheral blood, with minimal increases in CD4+CD25+Foxp3+ regulatory T cells. Daily administration of IL-15 resulted in persistently elevated plasma IL-15 levels and transient toxicity. Intermittent administration of IL-15 allowed clearance of IL-15 between doses and was safe for more than 3 weeks. These findings demonstrate that IL-15 has profound immunomodulatory properties distinct from those described for IL-2, and suggest that intermittent administration of IL-15 should be considered in clinical studies.

scholarly journals Limited Foxp3+ Regulatory T Cells Response During Acute Trypanosoma cruzi Infection Is Required to Allow the Emergence of Robust Parasite-Specific CD8+ T Cell Immunity

2018 ◽  
Vol 9 ◽  
Author(s):  
Cintia L. Araujo Furlan ◽  
Jimena Tosello Boari ◽  
Constanza Rodriguez ◽  
Fernando P. Canale ◽  
Facundo Fiocca Vernengo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Trypanosoma Cruzi ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Cruzi Infection

Dendritic Cell-Induced T Cell Non-Responsiveness Is Mediated by FOXP3+ and TGF-beta+IL-10+ CD4+ T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3891-3891
Author(s):  
Zwi N. Berneman ◽  
Nathalie Cools ◽  
Viggo F.I. Van Tendeloo ◽  
Marc Lenjou ◽  
Griet Nijs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
T Cell Immunity ◽  
Tgf Beta ◽  
Cell Immunity

Abstract Dendritic cells (DC), the professional antigen presenting cells of the immune system, exert important functions both in induction of T cell immunity as well as of tolerance. Previously, it was accepted that the main function of immature DC (iDC) in their in vivo steady state condition is to maintain peripheral tolerance to self-antigens and that these iDC mature upon encounter of so-called danger signals and subsequently promote T cell immunity. However, a growing body of experimental evidence now indicates that traditional DC maturation can no longer be used to distinguish between tolerogenic and immunogenic properties of DC. In this study, we compared the in vitro stimulatory capacity of immature DC (iDC), cytokine cocktail-matured DC (CC-mDC) and poly I:C-matured DC (pIC-mDC) in the absence and presence of antigen. All investigated DC types could induce at least 2 subsets of regulatory T cells. We observed a significant increase in both the number of functionally suppressive transforming growth factor (TGF)-beta+ interleukin (IL)-10+ T cells as well as of CD4+CD25+FOXP3+ T cells within DC/T cell co-cultures as compared to T cell cultures without DC. The induction of these regulatory T cells correlates with in vitro T cell non-responsiveness after co-culture with iDC and CC-mDC, while stimulation with pIC-mDC resulted in reproducible cytomegalovirus pp65 or influenza M1 matrix peptide-specific T cell activation as compared to control cultures in the absence of DC. In addition, the T cell non-responsiveness after stimulation with iDC was shown to be mediated by TGF-beta and IL-10. Moreover, the suppressive capacity of CD4+ T cells activated by iDC and CC-mDC was shown to be transferable when these CD4+ T cells were added to an established T cell response. In contrast, addition of CD4+ T cells stimulated by pIC-mDC made responder T cells refractory to their suppressive activity. In conclusion, we hypothesize that DC have a complementary role in inducing both regulatory T cells and effector T cells, where the final result of antigen-specific T cell activation will depend on the activation state of the DC. This emphasizes the need for proper DC activation when T cell immunity is the desired effect, especially when used in clinical trials.

scholarly journals Helicobacterpylori-Specific CD4+ CD25high Regulatory T Cells Suppress Memory T-Cell Responses to H. pylori in Infected Individuals

2003 ◽  
Vol 71 (4) ◽  
pp. 1755-1762 ◽  
Author(s):  
Anna Lundgren ◽  
Elisabeth Suri-Payer ◽  
Karin Enarsson ◽  
Ann-Mari Svennerholm ◽  
B. Samuel Lundin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Duodenal Mucosa ◽  
Peptic Ulcers ◽  
Memory Cells ◽  
Cell Responses ◽  
H Pylori

ABSTRACT Helicobacter pylori colonizes the gastric and duodenal mucosa. The infection normally persists for life and causes peptic ulcers and gastric cancer in a subset of infected individuals. We hypothesized that the inability to clear the infection may be a consequence of H. pylori-specific regulatory T cells that actively suppress T-cell responses. Therefore, we characterized the T-cell responses to H. pylori in H. pylori-infected individuals without any subjective symptoms and in uninfected control subjects and investigated the role of regulatory CD4+ CD25high T cells during infection. The stimulation of CD4+ peripheral blood T cells with monocyte-derived dendritic cells pulsed with a membrane preparation of H. pylori resulted in proliferation and gamma interferon production in both infected and uninfected individuals. Sorted memory cells from infected individuals responded less than cells from uninfected subjects, and the unresponsiveness could be abolished by depletion of CD4+ CD25high regulatory T cells or the addition of interleukin 2. Furthermore, CD4+ CD25high T cells suppressed H. pylori-induced responses in cocultures with CD25low/− cells. Tetanus toxoid induced comparable responses in memory cells from infected and uninfected individuals in both the presence and the absence of regulatory T cells, suggesting that the suppression was H. pylori specific. In conclusion, we have shown that H. pylori-infected individuals have impaired memory CD4+ T-cell responses to H. pylori that are linked to the presence of H. pylori-specific regulatory T cells that actively suppress the responses.

Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 4260-4267 ◽  
Author(s):  
Petra Hoffmann ◽  
Ruediger Eder ◽  
Tina J. Boeld ◽  
Kristina Doser ◽  
Biserka Piseshka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Lines ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Solid Organ ◽  
Cell Therapies ◽  
In Vitro Expansion

Abstract Thymus-derived CD4+CD25+ regulatory T cells suppress autoreactive CD4+ and CD8+ T cells and thereby protect from autoimmunity. In animal models, adoptive transfer of CD4+CD25+ regulatory T cells has been shown to prevent and even cure autoimmune diseases as well as pathogenic alloresponses after solid organ and stem-cell transplantations. We recently described methods for the efficient in vitro expansion of human regulatory T cells for clinical applications. We now demonstrate that only CCR7- and L-selectin (CD62L)–coexpressing cells within expanded CD4+CD25high T cells maintain phenotypic and functional characteristics of regulatory T cells. Further analysis revealed that these cells originate from CD45RA+ naive cells within the CD4+CD25high T-cell compartment, as only this subpopulation homogeneously expressed CD62L, CCR7, cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), and forkhead box P3 (FOXP3), produced no inflammatory cytokines and maintained robust suppressive activity after expansion. In contrast, cell lines derived from CD45RA– memory-type CD4+CD25high T cells lost expression of lymph node homing receptors CCR7 and CD62L, contained interleukin-2 (IL-2) and interferon-γ (IFN-γ) as well as IL-10–secreting cells, showed only moderate suppression and, most importantly, did not maintain FOXP3 expression. Based on these unexpected findings, we suggest that isolation and expansion of CD45RA+ naive CD4+ CD25high T cells is the best strategy for adoptive regulatory T (Treg)–cell therapies.

Initial depletion of regulatory T cells: the missing solution to preserve the immune functions of T lymphocytes designed for cell therapy

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 381-388 ◽  
Author(s):  
Mariana Mesel-Lemoine ◽  
Mustapha Cherai ◽  
Sabine Le Gouvello ◽  
Maude Guillot ◽  
Virginie Leclercq ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Therapy ◽  
Cell Cultures ◽  
Interleukin 2 ◽  
Culture Conditions ◽  
Immune Functions ◽  
T Cell Therapy ◽  
Cells Cultured

Abstract We investigated the causes of the altered functionality of T cells cultured under conditions designed for cell and gene therapy and the strategies to prevent their defects. We first showed that human T cells cultured for 6 days with anti-CD3 ± anti-CD28 antibodies and interleukin-2 presented a 50% decrease of their proliferative responses to allogeneic or recall antigens. Similarly, day-6 cultured murine T cells completely lost their capacity to reject allogeneic skin grafts and to provoke graft-versus-host disease (GVHD) when infused into irradiated semi-allogeneic mice. Interestingly, injection of higher amounts of cultured T cells restored GVHD induction. Moreover, depletion of CD25+ cells prior to T-cell cultures can prevent these deficiencies both in mice and humans. Therefore, we demonstrated that culture conditions used for T-cell therapy preferentially activated and expanded regulatory T cells (Treg's). Thus, we showed that dividing cells sorted from T-cell cultures strongly suppressed the proliferation of autologous T cells in response to allogeneic stimulation. An increased detection of Foxp3 at mRNA and protein levels in the cultures confirmed the Treg expansion. Overall, we demonstrate that T-cell cultures promote Treg expansion over effector T cells, leading to deleterious immune functions, and that this imbalance can be prevented by an initial depletion of CD25+ cells.

scholarly journals Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3096-3103 ◽  
Author(s):  
Kenrick Semple ◽  
Antony Nguyen ◽  
Yu Yu ◽  
Honglin Wang ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Specific Protein ◽  
Cell Immunity ◽  
Cd28 Costimulation

Abstract CD28 costimulation is required for the generation of naturally derived regulatory T cells (nTregs) in the thymus through lymphocyte-specific protein tyrosine kinase (Lck) signaling. However, it is not clear how CD28 costimulation regulates the generation of induced Tregs (iTregs) from naive CD4 T-cell precursors in the periphery. To address this question, we induced iTregs (CD25+Foxp3+) from naive CD4 T cells (CD25−Foxp3−) by T-cell receptor stimulation with additional transforming growth factorβ (TGFβ) in vitro, and found that the generation of iTregs was inversely related to the level of CD28 costimulation independently of IL-2. Using a series of transgenic mice on a CD28-deficient background that bears wild-type or mutated CD28 in its cytosolic tail that is incapable of binding to Lck, phosphoinositide 3-kinase (PI3K), or IL-2–inducible T-cell kinase (Itk), we found that CD28-mediated Lck signaling plays an essential role in the suppression of iTreg generation under strong CD28 costimulation. Furthermore, we demonstrate that T cells with the CD28 receptor incapable of activating Lck were prone to iTreg induction in vivo, which contributed to their reduced ability to cause graft-versus-host disease. These findings reveal a novel mechanistic insight into how CD28 costimulation negatively regulates the generation of iTregs, and provide a rationale for promoting T-cell immunity or tolerance by regulating Tregs through targeting CD28 signaling.

Strong CD28 Costimulation Suppresses Induction of Regulatory T Cells From Naïve Precursors through Lck Signaling.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3728-3728
Author(s):  
Kenrick Semple ◽  
Antony Nguyen ◽  
Yu Yu ◽  
Claudio Anasetti ◽  
Xue-Zhong Yu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Conflicts Of Interest ◽  
Graft Versus Host ◽  
Cell Immunity ◽  
Cd28 Costimulation ◽  
Insight Into

Abstract Abstract 3728 CD28 costimulation is required for the generation of naturally-derived regulatory T cells (nTregs) in the thymus through Lck-signaling. However, it is not clear how CD28 costimulation regulates the generation of induced Tregs (iTregs) from naïve CD4 T-cell precursors in the periphery. To address this question, we induced iTregs (CD25+Foxp3+) from naïve CD4 T cells (CD25−Foxp3−) by TCR-stimulation with additional TGFβ in vitro, and found that the generation of iTregs was inversely related to the level of CD28 costimulation independently of IL-2. By using a series of transgenic mice on CD28-deficient background that bears WT CD28 or mutated CD28 in its cytosolic tail incapable of binding to Lck, PI3K or Itk, we found that CD28-mediated Lck-signaling plays an essential role in the suppression of iTreg generation under strong CD28 costimulation. Furthermore, we demonstrate that T cells with the CD28 receptor incapable of activating Lck were prone to iTreg induction in vivo, which contributed to their reduced ability to cause graft-versus-host disease. These findings reveal a novel mechanistic insight into how CD28 costimulation negatively regulates the generation of iTregs, and provide the rationale for promoting T-cell immunity or tolerance by regulating Tregs through targeting CD28-signaling. Disclosures: No relevant conflicts of interest to declare.

Induction of allopeptide-specific human CD4+CD25+ regulatory T cells ex vivo

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2180-2186 ◽  
Author(s):  
Shuiping Jiang ◽  
Niels Camara ◽  
Giovanna Lombardi ◽  
Robert I. Lechler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Line ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Cell Lineage ◽  
Human Leukocyte ◽  
Regulatory Cells ◽  
Antigen Specificity

Abstract Although CD4+CD25+ regulatory T cells are pivotal in the prevention of autoimmunity and appear to mediate transplantation tolerance, little is known concerning their antigen specificity. Here we describe the induction of a human CD4+CD25+ regulatory T-cell line specific for a defined peptide alloantigen (human leukocyte antigen A2 [HLA-A2] 138-170) by priming purified CD4+CD25+ cells ex vivo. The regulatory cells were anergic and retained their ability to suppress antigen-driven responses of CD4+CD25– cells. They inhibited not only interleukin 2 (IL-2) secretion by CD4+CD25– T cells specific for the same peptide but also direct alloresponse of naive CD4+CD25– T cells stimulated by semiallogeneic dendritic cells (DCs) in the presence of the peptide (“linked suppression”). They also suppressed the response of CD4+ T cells specific for viral and bacterial antigens. The suppressive T-cell line showed sustained high CD25 expression. These findings suggest that peripheral CD4+CD25+ regulatory cells are a precommitted cell lineage from which cells with specificity for non–self-peptides can be selected. This may pave the way for inducing and expanding peptide antigen-specific regulatory T cells ex vivo for cell therapy in transplantation, allergy, and autoimmune disease.

scholarly journals Tissue-resident CD4+ T helper cells assist protective respiratory mucosal B and CD8+ T cell memory responses

2020 ◽  
Author(s):  
Young Min Son ◽  
In Su Cheon ◽  
Yue Wu ◽  
Chaofan Li ◽  
Zheng Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Helper Cells ◽  
Cell Formation ◽  
Influenza Virus Infection ◽  
T Helper ◽  
Helper Cells ◽  
Mucosal Tissues ◽  
Cell Immunity ◽  
Cd8 T Cell Memory

AbstractThe roles of CD4+ T helper cells (TH) in shaping localized memory B and CD8+ T cell immunity in the mucosal tissues are largely unexplored. Here, we report that lung TH cells provide local assistance for the optimal development of tissue-resident memory B (BRM) and CD8+ T (TRM) cells following the resolution of primary influenza virus infection. We identify a population of tissue-resident CD4+ TH (aka TRH) cells that co-exhibit follicular T helper (TFH) and TRM cell features and mediate local help of CD4+ T cells to B and CD8+ T cells. Optimal TRH cell formation requires lung B cells and transcription factors involved in TFH or TRM development. Further, we show that TRH cells deliver local help to B and CD8 T cells through CD40L and IL-21-dependent mechanisms. Our data have uncovered a new tissue-resident TH cell population that is specialized in assisting the development of mucosal protective B and CD8+ T cell responses in situ.

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