scholarly journals Human MHC Class I-restricted high avidity CD4+T cells generated by co-transfer of TCR and CD8 mediate efficient tumor rejection in vivo

2013 ◽  
Vol 2 (1) ◽  
pp. e22590 ◽  
Author(s):  
Shao-An Xue ◽  
Liquan Gao ◽  
Maryam Ahmadi ◽  
Sara Ghorashian ◽  
Rafael D Barros ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd4 T Cells ◽  
Tumor Rejection ◽  
Class I ◽  
High Avidity

scholarly journals MHC-class I-restricted CD4 T cells: a nanomolar affinity TCR has improved anti-tumor efficacy in vivo compared to the micromolar wild-type TCR

2012 ◽  
Vol 62 (2) ◽  
pp. 359-369 ◽  
Author(s):  
Carolina M. Soto ◽  
Jennifer D. Stone ◽  
Adam S. Chervin ◽  
Boris Engels ◽  
Hans Schreiber ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd4 T Cells ◽  
Class I ◽  
Wild Type

Endogenous T Cell Receptors Drive Non-Specific Suppression by Foxp3 MHC Class I-Restricted T Cell Receptor-Transduced Polyclonal CD4+ T Cells in Models of Graft-Versus-Host Disease.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3152-3152
Author(s):  
Benjamin J Uttenthal ◽  
Emma Nicholson ◽  
Ben Carpenter ◽  
Sara Ghorashian ◽  
Graham P Wright ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cd4 T Cells ◽  
Class I ◽  
Graft Versus Host ◽  
Specific Suppression ◽  
Mhc Class I Molecule

Abstract Abstract 3152 Alloreactive immune responses directed against malignant cells in recipients of allogeneic hematopoietic stem cell transplants are able to cure patients with hematological cancers. However, such immune responses may cause severe morbidity when directed against healthy recipient tissue, resulting in graft-versus-host disease (GvHD). Naturally occurring regulatory T cells (Tregs) are CD4+ T cells characterized by their expression of the transcription factor Foxp3. Whilst adoptively transferred polyclonal Tregs suppress GvHD in several murine models, their lack of specificity may compromise beneficial immunity against malignancy or infection. The generation of MHC class I-restricted, alloantigen-specific Tregs would allow them to recognize antigen presented directly on GvHD target tissues, concentrating their sites of activation at these tissues and possibly reducing the potential for non-specific immune suppression. We have generated ‘converted’ Tregs through retroviral transfer of genes encoding Foxp3 and specific MHC class I-restricted T cell receptors (TCRs) into polyclonal conventional CD4+ T cells. We used the 2C-TCR, which recognizes the MHC class I molecule H-2Ld, expressed in Balb/c and other H-2d mice, in complex with the ubiquitously expressed peptide p2Ca; and the MH-TCR, which recognizes the MHC class I molecule H-2Db, expressed in B6 and other H-2b mice, in complex with the male peptide WMHHNMDLI. In vitro, Foxp3 2C-TCR-transduced B6 polyclonal CD4+ T cells were hyporesponsive to stimulation and suppressed the alloreactive proliferative response of B6 CD4+ and CD8+ T cells to Balb/c splenocytes, consistent with the acquisition of regulatory function. When adoptively transferred to lethally irradiated Balb/c recipients of MHC-mismatched B6 bone marrow and conventional T cells, Foxp3 2C-TCR-transduced B6 polyclonal CD4+ T cells significantly reduced early proliferation of donor T cells, weight loss and GvHD score in the recipients. Similarly, polyclonal CD4+ T cells transduced with Foxp3 and the MH-TCR caused marked suppression of allogeneic responses both in vitro and in vivo. However, while both the 2C-TCR and the MH-TCR conferred specificity to their cognate antigens in vitro, the potent suppression in these in vivo models was independent of the cognate antigen for the transduced TCRs. This non-specific suppression was markedly reduced when class I-restricted TCRs were transduced into OT-II Rag1-/- CD4+ T cells that are transgenic for a single endogenous TCR. These findings demonstrate an important role for the endogenous TCRs in driving non-specific suppression by polyclonal CD4+ T cells transduced with Foxp3 and class I-restricted TCRs, and suggest that strategies to downregulate endogenous TCRs will be required to achieve antigen-specific suppression in TCR gene-modified regulatory T cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficient Targeting of Protein Antigen to the Dendritic Cell Receptor DEC-205 in the Steady State Leads to Antigen Presentation on Major Histocompatibility Complex Class I Products and Peripheral CD8+ T Cell Tolerance

2002 ◽  
Vol 196 (12) ◽  
pp. 1627-1638 ◽  
Author(s):  
Laura Bonifaz ◽  
David Bonnyay ◽  
Karsten Mahnke ◽  
Miguel Rivera ◽  
Michel C. Nussenzweig ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Steady State ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Class I ◽  
Histocompatibility Complex ◽  
Dc Maturation

To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal αDEC-205 antibody, was presented by CD11c+ lymph node DCs, but not by CD11c− cells, to OVA-specific, CD4+ and CD8+ T cells. Receptor-mediated presentation was at least 400 times more efficient than unconjugated OVA and, for MHC class I, the DCs had to express transporter of antigenic peptides (TAP) transporters. When αDEC-205:OVA was injected subcutaneously, OVA protein was identified over a 4–48 h period in DCs, primarily in the lymph nodes draining the injection site. In vivo, the OVA protein was selectively presented by DCs to TCR transgenic CD8+ cells, again at least 400 times more effectively than soluble OVA and in a TAP-dependent fashion. Targeting of αDEC-205:OVA to DCs in the steady state initially induced 4–7 cycles of T cell division, but the T cells were then deleted and the mice became specifically unresponsive to rechallenge with OVA in complete Freund's adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus via CD40, together with αDEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic αCD40 antibody produced large amounts of interleukin 2 and interferon γ, acquired cytolytic function in vivo, emigrated in large numbers to the lung, and responded vigorously to OVA rechallenge. Therefore, DEC-205 provides an efficient receptor-based mechanism for DCs to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation.

Alloreactive CD8 T Cells Process and Present Acquired MHC Class I Alloantigen To Indirect Pathway Helper CD4 T Cells.

2014 ◽  
Vol 98 ◽  
pp. 310
Author(s):  
E. Wlodek ◽  
A. Jason ◽  
K. Saeb-Parsy ◽  
M. Chhubra ◽  
G. Pettigrew
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Class I ◽  
Indirect Pathway

scholarly journals Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection.

1987 ◽  
Vol 166 (6) ◽  
pp. 1716-1733 ◽  
Author(s):  
J S Weber ◽  
G Jay ◽  
K Tanaka ◽  
S A Rosenberg
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Interleukin 2 ◽  
Class I ◽  
High Dose ◽  
Class I Mhc ◽  
High Doses ◽  
I Gene

We have shown that two weakly immunogenic MCA sarcomas developed in our laboratory that are sensitive to high-dose IL-2 immunotherapy express class I MHC in vivo and in vitro. Two nonimmunogenic MCA sarcomas are relatively insensitive to IL-2 therapy and express minimal or no class I MHC molecules in vivo and in vitro. To study the role of MHC in the therapy of tumors with IL-2, a class I-deficient murine melanoma, B16BL6, was transfected with the Kb class I gene. Expression of class I MHC rendered B16BL6 advanced pulmonary macrometastases sensitive to IL-2 immunotherapy. 3-d micrometastases of CL8-2, a class I transfected clone of B16BL6, were significantly more sensitive to IL-2 therapy than a control nontransfected line. Expression of Iak, a class II MHC molecule, had no effect on IL-2 therapy of transfectant pulmonary micrometastases in F1 mice. By using lymphocyte subset depletion with mAbs directed against Lyt-2, therapy of class I transfectant macrometastases with high-dose IL-2 was shown to involve an Lyt-2 cell. In contrast, regression of micrometastases treated with low-dose IL-2 involved Lyt-2+ cells, but regression mediated by high doses of IL-2 did not. We hypothesize that both LAK and Lyt-2+ T cells effect IL-2-mediated elimination of micrometastases, but only Lyt-2+ T cells are involved in macrometastatic regression. Low doses of IL-2 stimulate Lyt-2+ cells to eliminate class I-expressing micrometastases, but high doses of IL-2 can recruit LAK cells to mediate regression of micrometastases independent of class I expression. Only high-dose IL-2, mediating its effect predominantly via Lyt-2+ cells, is capable of impacting on MHC class I-expressing macrometastases. Macrometastases devoid of class I MHC antigens appear to be resistant to IL-2 therapy.

scholarly journals gp100/pmel 17 Is a Murine Tumor Rejection Antigen: Induction of “Self”-reactive, Tumoricidal T Cells Using High-affinity, Altered Peptide Ligand

1998 ◽  
Vol 188 (2) ◽  
pp. 277-286 ◽  
Author(s):  
Willem W. Overwijk ◽  
Allan Tsung ◽  
Kari R. Irvine ◽  
Maria R. Parkhurst ◽  
Theresa J. Goletz ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Tissue Differentiation ◽  
Tumor Rejection ◽  
Class I ◽  
Peptide Ligand ◽  
Altered Peptide Ligand ◽  
Target Tissue ◽  
Differentiation Antigens ◽  
High Affinity

Many tumor-associated antigens are nonmutated, poorly immunogenic tissue differentiation antigens. Their weak immunogenicity may be due to “self”-tolerance. To induce autoreactive T cells, we studied immune responses to gp100/pmel 17, an antigen naturally expressed by both normal melanocytes and melanoma cells. Although a recombinant vaccinia virus (rVV) encoding the mouse homologue of gp100 was nonimmunogenic, immunization of normal C57BL/6 mice with the rVV encoding the human gp100 elicited a specific CD8+ T cell response. These lymphocytes were cross-reactive with mgp100 in vitro and treated established B16 melanoma upon adoptive transfer. To understand the mechanism of the greater immunogenicity of the human version of gp100, we characterized a 9-amino acid (AA) epitope, restricted by H-2Db, that was recognized by the T cells. The ability to induce specific T cells with human but not mouse gp100 resulted from differences within the major histocompatibility complex (MHC) class I–restricted epitope and not from differences elsewhere in the molecule, as was evidenced by experiments in which mice were immunized with rVV containing minigenes encoding these epitopes. Although the human (hgp10025–33) and mouse (mgp10025–33) epitopes were homologous, differences in the three NH2-terminal AAs resulted in a 2-log increase in the ability of the human peptide to stabilize “empty” Db on RMA-S cells and a 3-log increase in its ability to trigger interferon γ release by T cells. Thus, the fortuitous existence of a peptide homologue with significantly greater avidity for MHC class I resulted in the generation of self-reactive T cells. High-affinity, altered peptide ligands might be useful in the rational design of recombinant and synthetic vaccines that target tissue differentiation antigens expressed by tumors.

IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

Blood ◽  
2012 ◽  
Vol 119 (6) ◽  
pp. 1407-1417 ◽  
Author(s):  
Francesca Spadaro ◽  
Caterina Lapenta ◽  
Simona Donati ◽  
Laura Abalsamo ◽  
Vincenzo Barnaba ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Tumor Development ◽  
Class I ◽  
Cross Presentation ◽  
The Cross ◽  
Human Dendritic Cells

Abstract Cross-presentation allows antigen-presenting cells to present exogenous antigens to CD8+ T cells, playing an essential role in controlling infections and tumor development. IFN-α induces the rapid differentiation of human mono-cytes into dendritic cells, known as IFN-DCs, highly efficient in mediating cross-presentation, as well as the cross-priming of CD8+ T cells. Here, we have investigated the mechanisms underlying the cross-presentation ability of IFN-DCs by studying the intracellular sorting of soluble ovalbumin and nonstructural-3 protein of hepatitis C virus. Our results demonstrate that, independently from the route and mechanism of antigen entry, IFN-DCs are extraordinarily competent in preserving internalized proteins from early degradation and in routing antigens toward the MHC class-I processing pathway, allowing long-lasting, cross-priming capacity. In IFN-DCs, both early and recycling endosomes function as key compartments for the storage of both antigens and MHC-class I molecules and for proteasome- and transporter-associated with Ag processing–dependent auxiliary cross-presentation pathways. Because IFN-DCs closely resemble human DCs naturally occurring in vivo in response to infections and other danger signals, these findings may have important implications for the design of vaccination strategies in neoplastic or chronic infectious diseases.

T Cell Receptor Gene Transfer to Produce MHC Class I-Restricted CD4 Helper T Cells: Implications for Immunotherapy of Leukaemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5262-5262
Author(s):  
Emma Morris ◽  
Aristotle Tsallios ◽  
Gavin Bendle ◽  
Shao-an Xue ◽  
Hans Stauss
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd4 T Cells ◽  
Tumour Cells ◽  
Class I ◽  
Helper T Cells ◽  
Specific Response ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Irrelevant Peptide

Abstract CD4 helper T cells play a critical role in the anti-tumour immune response. Cytokines secreted by CD4 T cells can have a direct effect on tumour cells and provide help for CTL priming and effector function. In this study we tested if it was possible to generate MHC class I-restricted helper T cells by retroviral TCR gene transfer into CD4 lymphocytes. Methods: We used a TCR (utilising V11) that recognises the influenza virus A nucleoprotein (NP366–379) peptide in the context of murine Db MHC class I. Murine splenocytes were isolated from C57BL/6 mice (H2b) and activated with conconavalin A and IL-7, and after 48 hours transduced with the pMX-TCR-IRES-TCR retroviral vector. The transduced splenocytes were then cultured in the presence of IL2 for a further 48 hours before staining with anti-murine CD4, CD8 and V11 antibodies and sorting into CD4+ V11+ and CD8+ V11+ populations. Sorted cells were expanded for a further 48–72 hours prior to functional assays. Functional Assays: Purified TCR-transduced (TCR-Td) CD8+ cells and purified TCR-Td CD4+ cells were tested for IFN secretion in response to dendritic cells (DCs) pulsed with NP peptide, an irrelevant peptide (pMDM100) or no peptide. Further experiments examined IFN secretion in response to peptide-loaded tumour cells (EL4 murine lymphoma cells) or transfected tumour cells expressing NP endogenously. Secretion of IFN was measured by ELISA. Results: (1) Antigen-specific IFN secretion was observed by both CD8+ (100% purity) and CD4+ cells (99.93% purity) expressing the class I-restricted TCR when incubated with peptide-loaded DCs. When tested with no peptide or irrelevant peptide, no IFN secretion was observed. The CD8+ cells were more sensitive, recognizing lower concentrations of peptide (10pM) than CD4+ cells (100pM). With peptide-coated EL4 tumour cells as stimulator cells, CD8+ cells showed a peptide-specific response. In contrast, the TCR-Td CD4+ cells were only able to elicit a weak peptide-specific response. Similarly, TCR-Td CD8+ cells were able to recognise NP transfected EL4 tumour cells (EL4NP68), whereas the CD4+ cells were unable to. However, the addition of syngeneic DCs restored the CD4+ cell response to NP transfected EL4 tumour cells to one equivalent to that seen with the TCR-Td CD8+ populations (Table 1). Summary: We have demonstrated that it is feasible to generate MHC class I-restricted CD4+ helper T cells, that are specific for peptide epitopes presented in the context of MHC class I. The CD4+ T cells can recognise antigen-expressing tumour cells in the presence of professional APC, such as DCs. The mechanism by which APC restore tumour recognition may involve trans-costimulation or cross presentation. The data suggest that class I-restricted CD4+ T cells may be able to contribute to enhanced anti-tumour immunity. αββββγγγγγβ γIFN Secretion (ng/ml) After Stimulation with DCs or Tumour Cells T Cell (Responder Cell) Stimulator Cell/s No Peptide NP (100nM) pMDM100 (100nM) Abbreviations: ND not done; DC, EL4 and EL4NP68 as indicated in text. TCR-Td CD8+ DCs 0.1 163.2 0.7 TCR-Td CD8+ EL4 0.1 19.9 0.2 TCR-Td CD8+ EL4NP68 16.6 ND ND TCR-Td CD8+ EL4NP68 + DCs 31.2 ND ND TCR-Td CD4+ DCs 0.1 163.9 0.2 TCR-Td CD4+ EL4 0.1 0.8 0.0 TCR-Td CD4+ EL4NP68 0.2 ND ND TCR-Td CD4+ EL4NP68 + DCs 25.3 ND ND

scholarly journals Constitutive versus Activation-dependent Cross-Presentation of Immune Complexes by CD8+ and CD8− Dendritic Cells In Vivo

2002 ◽  
Vol 196 (6) ◽  
pp. 817-827 ◽  
Author(s):  
Joke M.M. den Haan ◽  
Michael J. Bevan
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Immune Complexes ◽  
Class I ◽  
Cross Presentation ◽  
Deficient Mice ◽  
Mhc Class I Molecules

Murine splenic dendritic cells (DCs) can be divided into two subsets based on CD8α expression, but the specific role of each subset in stimulation of T cells is largely unknown. An important function of DCs is the ability to take up exogenous antigens and cross-present them in the context of major histocompatibility complex (MHC) class I molecules to CD8+ T cells. We previously demonstrated that, when cell-associated ovalbumin (OVA) is injected into mice, only the CD8+ DC subset cross-presents OVA in the context of MHC class I. In contrast to this selectivity with cell-associated antigen, we show here that both DC subsets isolated from mice injected with OVA/anti-OVA immune complexes (OVA-IC) cross-present OVA to CD8+ T cells. The use of immunoglobulin G Fc receptor (FcγR) common γ-chain–deficient mice revealed that the cross-presentation by CD8− DCs depended on the expression of γ-chain–containing activating FcγRs, whereas cross-presentation by CD8+ DCs was not reduced in γ-chain–deficient mice. These results suggest that although CD8+ DCs constitutively cross-present exogenous antigens in the context of MHC class I molecules, CD8− DCs only do so after activation, such as via ligation of FcγRs. Cross-presentation of immune complexes may play an important role in autoimmune diseases and the therapeutic effect of antitumor antibodies.

Sign in / Sign up

Export Citation Format

Share Document