Cysteinyl leukotrienes mediate lymphokine killer activity induced by NKG2D and IL-15 in cytotoxic T cells during celiac disease

Eicosanoids are inflammatory mediators that play a key but incompletely understood role in linking the innate and adaptive immune systems. Here, we show that cytotoxic effector T cells (CTLs) are capable of both producing and responding to cysteinyl leukotrienes (CystLTs), allowing for the killing of target cells in a T cell receptor–independent manner. This process is dependent on the natural killer receptor NKG2D and exposure to IL-15, a cytokine induced in distressed tissues. IL-15 and NKG2D signaling drives the up-regulation of key enzymes implicated in the synthesis of CystLTs, as well as the expression of CystLT receptors, suggesting a positive feedback loop. Finally, although the CystLT pathway has been previously linked to various allergic disorders, we provide unexpected evidence for its involvement in the pathogenesis of celiac disease (CD), a T helper 1 cell–mediated enteropathy induced by gluten. These findings provide new insights into the cytolytic signaling pathway of NKG2D and the pathogenesis of organ-specific immune disorders. Furthermore, they suggest that the blockade of CystLT receptors may represent a potent therapeutic target for CD or potentially other autoimmune disorders in which NKG2D has been implicated.

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Specificity of cytotoxic T cells from athymic mice.

Journal of Experimental Medicine ◽

10.1084/jem.152.3.688 ◽

1980 ◽

Vol 152 (3) ◽

pp. 688-702 ◽

Cited By ~ 85

Author(s):

T Hünig ◽

M J Bevan

Keyword(s):

T Cells ◽

T Cell ◽

Nude Mice ◽

Germ Line ◽

Placental Transfer ◽

Cytotoxic T Lymphocyte ◽

Cytotoxic T Cells ◽

Cell Receptor ◽

Third Party ◽

Target Cells

In normal mice, self-H-2 antigens in the thymus have a profound influence on T cell specificity. We have therefore investigated the properties of cytotoxic T lymphocyte (CTL) precursors from athymic nude mice (5) with the notion that they may provide a model system for the study of T cells whose receptro specificity is closer to the germ-line-encoded repertoire. It was found that the precursors of nude CTL are, themselves, THy-1+ cells. The possibility that these nude t cells were derived from the phenotypically normal mother by placental transfer was ruled out. In the presence of T cell growth factor, nude CTL can be induced by polyclonal activation with concanavalin A or by stimulation with allogeneic or trinitrophenyl (TNP)-modified syngeneic stimulator cells, but not by stimulation with minor H antigens in the context of self-H-2. Alloreactive, nude CTL--like those from normal mice--recognize H-2K- and H-2D-region-encoded antigens in killer-target cell interactions, but, unlike normal CTL, did not cross-react on third-party target cells. Whereas the anti-TNP response of nude mice is H-2 restricted, it does not seem to be influenced by self-H-2 antigens in the same manner as in normal mice. This is suggested by the finding that the immunodominance of H-2k over H-2d in the anti-TNP-self response of normal (H-2d X H-2b)F1 mice is absent in (H-2d X H-2k)F1 nude mice. These observations are discussed in relation to the role of the thymus in the generation of the normal mature T cell receptor repertoire.

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Targeting CAR to the Peptide-MHC Complex Reveals Distinct Signaling Compared to That of TCR in a Jurkat T Cell Model

Cancers ◽

10.3390/cancers13040867 ◽

2021 ◽

Vol 13 (4) ◽

pp. 867

Author(s):

Ling Wu ◽

Joanna Brzostek ◽

Shvetha Sankaran ◽

Qianru Wei ◽

Jiawei Yap ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Model ◽

Cell Receptor ◽

Target Cells ◽

Tcr Signaling ◽

Barr Virus ◽

Car T ◽

Epstein Barr ◽

Lower Magnitude

Chimeric antigen receptor T cells (CAR-T) utilize T cell receptor (TCR) signaling cascades and the recognition functions of antibodies. This allows T cells, normally restricted by the major histocompatibility complex (MHC), to be redirected to target cells by their surface antigens, such as tumor associated antigens (TAAs). CAR-T technology has achieved significant successes in treatment of certain cancers, primarily liquid cancers. Nonetheless, many challenges hinder development of this therapy, such as cytokine release syndrome (CRS) and the efficacy of CAR-T treatments for solid tumors. These challenges show our inadequate understanding of this technology, particularly regarding CAR signaling, which has been less studied. To dissect CAR signaling, we designed a CAR that targets an epitope from latent membrane protein 2 A (LMP2 A) of the Epstein–Barr virus (EBV) presented on HLA*A02:01. Because of this, CAR and TCR signaling can be compared directly, allowing us to study the involvement of other signaling molecules, such as coreceptors. This comparison revealed that CAR was sufficient to bind monomeric antigens due to its high affinity but required oligomeric antigens for its activation. CAR sustained the transduced signal significantly longer, but at a lower magnitude, than did TCR. CD8 coreceptor was recruited to the CAR synapse but played a negligible role in signaling, unlike for TCR signaling. The distinct CAR signaling processes could provide explanations for clinical behavior of CAR-T therapy and suggest ways to improve the technology.

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Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells

Blood ◽

10.1182/blood-2003-06-2125 ◽

2004 ◽

Vol 103 (8) ◽

pp. 3065-3072 ◽

Cited By ~ 254

Author(s):

Michael R. Verneris ◽

Mobin Karami ◽

Jeanette Baker ◽

Anishka Jayaswal ◽

Robert S. Negrin

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Interleukin 2 ◽

Cell Receptor ◽

Malignant Cell ◽

Leukemic Cells ◽

Target Cells ◽

High Dose ◽

Effector Cells ◽

Nkg2d Expression

Abstract Activating and expanding T cells using T-cell receptor (TCR) cross-linking antibodies and interleukin 2 (IL-2) results in potent cytotoxic effector cells capable of recognizing a broad range of malignant cell targets, including autologous leukemic cells. The mechanism of target cell recognition has previously been unknown. Recent studies show that ligation of NKG2D on natural killer (NK) cells directly induces cytotoxicity, whereas on T cells it costimulates TCR signaling. Here we demonstrate that NKG2D expression is up-regulated upon activation and expansion of human CD8+ T cells. Antibody blocking, redirected cytolysis, and small interfering RNA (siRNA) studies using purified CD8+ T cells demonstrate that cytotoxicity against malignant target cells occurs through NKG2D-mediated recognition and signaling and not through the TCR. Activated and expanded CD8+ T cells develop cytotoxicity after 10 to 14 days of culture, coincident with the expression of the adapter protein DAP10. T cells activated and expanded in low (30 U/mL) and high (300 U/mL) concentrations of IL-2 both up-regulated NKG2D expression equally, but only cells cultured in high-dose IL-2 expressed DAP10 and were cytotoxic. Collectively these results establish that NKG2D triggering accounts for the majority of major histocompatibility complex (MHC)–unrestricted cytotoxicity of activated and expanded CD8+ T cells, likely through DAP10-mediated signaling. (Blood. 2004;103: 3065-3072)

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Cord blood comprises antigen-experienced T cells specific for maternal minor histocompatibility antigen HA-1

Blood ◽

10.1182/blood-2004-07-2832 ◽

2005 ◽

Vol 105 (4) ◽

pp. 1823-1827 ◽

Cited By ~ 59

Author(s):

Bregje Mommaas ◽

Janine A. Stegehuis-Kamp ◽

Astrid G. van Halteren ◽

Michel Kester ◽

Jürgen Enczmann ◽

...

Keyword(s):

T Cells ◽

Cord Blood ◽

Ex Vivo ◽

Cytotoxic T Cells ◽

Cord Blood Transplantation ◽

Human Leukocyte ◽

Leukemic Cells ◽

Target Cells ◽

Graft Versus Leukemia

AbstractUmbilical cord blood transplantation is applied as treatment for mainly pediatric patients with hematologic malignancies. The clinical results show a relatively low incidence of graft-versus-host disease and leukemia relapse. Since maternal cells traffic into the fetus during pregnancy, we questioned whether cord blood has the potential to generate cytotoxic T cells specific for the hematopoietic minor histocompatibility (H) antigen HA-1 that would support the graft-versus-leukemia effect. Here, we demonstrate the feasibility of ex vivo generation of minor H antigen HA-1-specific T cells from cord blood cells. Moreover, we observed pre-existing HA-1-specific T cells in cord blood samples. Both the circulating and the ex vivo-generated HA-1-specific T cells show specific and hematopoietic restricted lysis of human leukocyte antigen-A2pos/HA-1pos (HLA-A2pos/HA-1pos) target cells, including leukemic cells. The cord blood-derived HA-1-specific cytotoxic T cells are from child origin. Thus, the so-called naive cord blood can comprise cytotoxic T cells directed at the maternal minor H antigen HA-1. The apparent immunization status of cord blood may well contribute to the in vivo graft-versus-leukemia activity after transplantation. Moreover, since the fetus cannot be primed against Y chromosome-encoded minor H antigens, cord blood is an attractive stem cell source for male patients. (Blood. 2005;105:1823-1827)

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CD28-B7 interactions allow the induction of CD8+ cytotoxic T lymphocytes in the absence of exogenous help.

Journal of Experimental Medicine ◽

10.1084/jem.177.6.1791 ◽

1993 ◽

Vol 177 (6) ◽

pp. 1791-1796 ◽

Cited By ~ 182

Author(s):

F A Harding ◽

J P Allison

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cytotoxic T Cells ◽

Interleukin 2 ◽

Cell Receptor ◽

Histocompatibility Complex ◽

Necessary And Sufficient ◽

Additional Antigen

The activation requirements for the generation of CD8+ cytotoxic T cells (CTL) are poorly understood. Here we demonstrate that in the absence of exogenous help, a CD28-B7 interaction is necessary and sufficient for generation of class I major histocompatibility complex-specific CTL. Costimulation is required only during the inductive phase of the response, and not during the effector phase. Transfection of the CD28 counter receptor, B7, into nonstimulatory P815 cells confers the ability to elicit P815-specific CTL, and this response can be inhibited by anti-CD28 Fab or by the chimeric B7-binding protein CTLA4Ig. Anti-CD28 monoclonal antibody (mAb) can provide a costimulatory signal to CD8+ T cells when the costimulatory capacity of splenic stimulators is destroyed by chemical fixation. CD28-mediated signaling provokes the release of interleukin 2 (IL-2) from the CD8+ CTL precursors, as anti-CD28 mAb could be substituted for by the addition of IL-2, and an anti-IL-2 mAb can block the generation of anti-CD28-induced CTL. CD4+ cells are not involved in the costimulatory response in the systems examined. We conclude that CD8+ T cell activation requires two signals: an antigen-specific signal mediated by the T cell receptor, and an additional antigen nonspecific signal provided via a CD28-B7 interaction.

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Fas ligand mediates activation-induced cell death in human T lymphocytes.

Journal of Experimental Medicine ◽

10.1084/jem.181.1.71 ◽

1995 ◽

Vol 181 (1) ◽

pp. 71-77 ◽

Cited By ~ 625

Author(s):

M R Alderson ◽

T W Tough ◽

T Davis-Smith ◽

S Braddy ◽

B Falk ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Fas Ligand ◽

Significant Proportion ◽

Cell Receptor ◽

Target Cells ◽

Activated T Cells ◽

Activation Induced Cell Death ◽

Fas L

A significant proportion of previously activated human T cells undergo apoptosis when triggered through the CD3/T cell receptor complex, a process termed activation-induced cell death (AICD). Ligation of Fas on activated T cells by either Fas antibodies or recombinant human Fas-ligand (Fas-L) also results in cytolysis. We demonstrate that these two pathways of apoptosis are causally related. Stimulation of previously activated T cells resulted in the expression of Fas-L mRNA and lysis of Fas-positive target cells. Fas-L antagonists inhibited AICD of T cell clones and staphylococcus enterotoxin B (SEB)-specific T cell lines. The data indicate AICD in previously stimulated T cells is mediated by Fas/Fas-L interactions.

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Participation of the H-2 antigens of tumor cells in their lysis by syngeneic T cells.

Journal of Experimental Medicine ◽

10.1084/jem.143.3.601 ◽

1976 ◽

Vol 143 (3) ◽

pp. 601-614 ◽

Cited By ~ 67

Author(s):

J W Schrader ◽

G M Edelman

Keyword(s):

T Cells ◽

Tumor Cell ◽

Tumor Cells ◽

Target Cell ◽

Cytotoxic T Cells ◽

Hybrid Origin ◽

Target Cells ◽

Cytotoxic Lymphocytes ◽

Effector Cells

Cytotoxic T lymphocytes were generated in vitro against H-2 compatible or syngeneic tumor cells. In vitro cytotoxic activity was inhibited by specific anti-H2 sera, suggesting that H-2 antigens are involved in cell lysis. Two observations directly demonstrated the participation of the H-2 antigens on the tumor cells in their lysis by H-2-compatible T cells. First, coating of the H-2 antigens on the target tumor cell reduced the number of cells lysed on subsequent exposure to cytotoxic T cells. Second, when cytotoxic T cells were activated against an H-2 compatible tumor and assayed against an H-2-incompatible tumor, anti-H-2 serum that could bind to the target cell, but not to the cytotoxic lymphocyte, inhibited lysis. H-2 antigens were also shown to be present on the cytotoxic lymphocytes. Specific antisera reacting with these H-2 antigens, but not those of the target cell, failed to inhibit lysis when small numbers of effector cells were assayed against H-2-incompatible target cells or when effector cells of F1-hybrid origin and bearing two H-2 haplotypes were assayed against a tumor cell of one of the parental strains. These findings suggest that it is the H-2 antigens on the tumor cell and not those on the cytotoxic lymphocytes that are important in cell-mediated lysis of H-2-compatible tumor cells.

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Listeria monocytogenes-reactive T lymphocyte clones with cytolytic activity against infected target cells.

Journal of Experimental Medicine ◽

10.1084/jem.164.1.363 ◽

1986 ◽

Vol 164 (1) ◽

pp. 363-368 ◽

Cited By ~ 75

Author(s):

S H Kaufmann ◽

E Hug ◽

G De Libero

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

T Lymphocyte ◽

Cytotoxic T Cells ◽

Cytolytic Activity ◽

Target Cells ◽

Intracellular Bacteria ◽

Spleen Cells ◽

Ifn Gamma ◽

Cell Clones

Lyt-2+ T cell clones were established from Listeria monocytogenes-infected mice. The clones secreted IFN-gamma after stimulation with spleen cells from L. monocytogenes-infected mice plus IL-2. Spleen cells from normal mice were not stimulatory. Furthermore, cloned T cells lysed L. monocytogenes-infected macrophages. Cytolysis was antigen-specific and H-2K-restricted. These findings suggest a role for specific cytotoxic T cells in the immune response to intracellular bacteria.

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αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression

Journal of Personalized Medicine ◽

10.3390/jpm11090923 ◽

2021 ◽

Vol 11 (9) ◽

pp. 923

Author(s):

Josephine G. M. Strijker ◽

Ronja Pscheid ◽

Esther Drent ◽

Jessica J. F. van der Hoek ◽

Bianca Koopmans ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Transcriptional Profiling ◽

Γδ T Cells ◽

Cell Receptor ◽

Target Cells ◽

Γδ T Cell ◽

Mhc I ◽

Organization Analysis ◽

Αβ T Cells

Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients.

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