scholarly journals In Vivo Survival of  Viral Antigen–specific T Cells that Induce Experimental Autoimmune Encephalomyelitis

1998 ◽  
Vol 188 (9) ◽  
pp. 1725-1738 ◽  
Author(s):  
Rafael L. Ufret-Vincenty ◽  
Laura Quigley ◽  
Nancy Tresser ◽  
Seong Hee Pak ◽  
Ameer Gado ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Viral Antigen ◽  
Low Dose ◽  
Cell Clone ◽  
Viral Peptide ◽  
Autoreactive T Cell ◽  
T Cell Clone

A peptide derived from the human papillomavirus L2 protein is recognized by a myelin basic protein (MBP)-specific T cell clone from a multiple sclerosis patient and by MBP-specific autoantibodies purified from multiple sclerosis brain tissue. We now show in mice that low doses of this papillomavirus peptide were optimal in selecting a subpopulation of papillomavirus peptide–specific T cells that cross-reacted with MBP(87–99) and with an unrelated viral peptide derived from the BSLF1 protein of Epstein-Barr virus (EBV). These low dose viral peptide– specific T cell lines were highly encephalitogenic. Splenocytes from mice transferred with viral peptide–specific T cells showed a vigorous response to both the papillomavirus and MBP peptides, indicating that viral antigen–specific T cells survived for a prolonged time in vivo. The EBV peptide, unable to prime and select an autoreactive T cell population, could still activate the low dose papillomavirus peptide–specific cells and induce central nervous system (CNS) autoimmunity. Cytokine profiles of papillomavirus peptide–specific encephalitogenic T cells and histopathology of CNS lesions resembled those induced by MBP. These results demonstrate conserved aspects in the recognition of the self-antigen and a cross-reactive viral peptide by human and murine MBP-specific T cell receptors. We demonstrate that a viral antigen, depending on its nature, dose, and number of exposures, may select autoantigen-specific T cells that survive in vivo and can trigger autoimmune disease after adoptive transfer.

scholarly journals MHC-restricted minimal regulatory circuit initiated by a class II-autoreactive T cell clone.

1987 ◽  
Vol 165 (5) ◽  
pp. 1284-1295 ◽  
Author(s):  
K Sano ◽  
I Fujisawa ◽  
R Abe ◽  
Y Asano ◽  
T Tada
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Clone ◽  
Class Ii ◽  
Secondary Antibody ◽  
Th Cells ◽  
Mhc Restriction ◽  
Autoreactive T Cell ◽  
Regulatory Circuit ◽  
T Cell Clone

The in vivo administration of a self-class II-reactive Th clone MS202 derived from C3H into syngeneic mice resulted in the suppression of both primary and early secondary antibody responses against T cell-dependent antigens. The suppression was due to the generation of antigen-nonspecific Ts cells in the recipient, as the splenic T cells from the mice treated with MS202 were able to strongly suppress the in vitro secondary antibody response of primed syngeneic spleen cells. The dose-response curve of suppression indicated the generation of an effector type Ts that directly suppressed Th. The surface phenotype of Ts was Ly-1+,2-, L3T4+, I-J-. The presence of Ly-1+,2+ T cells was not required to induce the suppression. The suppression was strictly restricted to H-2k, as F1 Ts cells were able to suppress the response of C3H but not of B6 B cells helped by the same F1 Th cells. The experiments with chimeric mice indicated that the direct target of Ts is an MHC-restricted Th but not a B cell or APC. The results indicate the existence of a minimal regulatory circuit where an MHC-restricted Th induces a preprogrammed Ts that in turn directly suppresses Th with the same MHC-restriction specificity. The induction of and suppression by Ts appeared to be due to the direct recognition of MHC restriction sites of Th cells.

Cytotoxicity Is Not Required for the Anti-Leukemia Efficacy of Human H-Y-Specific CD4+ T Lymphocytes In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3553-3553
Author(s):  
Attilio Bondanza ◽  
Lothar Hambach ◽  
Zohara Aghai ◽  
Monica Casucci ◽  
Bart Nijmeijer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Clone ◽  
Scid Mice ◽  
Helper T Cell ◽  
T Cell Clone ◽  
Control Clone

Abstract Abstract 3553 Poster Board III-490 Introduction Minor histocompatibility antigens (mHag) play a major role in the graft-versus-leukemia (GvL) effect following HLA-matched allogeneic hemopoietic cell transplantation (allo-HCT). Clinically, the GvL effect coincides with the emergence of mHag-specific CD8+ cytotoxic T lymphocytes (CTL). Experimentally, targeting a single mHag with human CD8+ CTL has a major anti-leukemia effect in NOD/scid mice. Altogether, these observations suggest that mHag-specific cytotoxicity by CD8+ T cells is an important component of the GvL effect. In contrast, little is known on the contribution of mHag-specific CD4+ T cells. Female-to-male allo-HCT is characterized by a low rate of leukemia relapse, indicating that H-Y-encoded mHag are potent leukemia-regression antigens. Earlier, we described a DRB3*0301-restricted H-Y mHag epitope inducing CD4+ helper T-cell responses in H-Y-mismatched HLA-matched allo-HCT. Aim: The aim of this study is to elucidate the role of mHag-specific human CD4+ T lymphocytes on the GvL effect. Methods The ALL-CM leukemia cell line, derived from a male (i.e. H-Y+) HLA-A0201+, DRB30301+ patient, reproducibly engrafts in NOD/scid mice after administration of 10×106 cells. Both an HLA-A0201-restricted H-Y-specific CD8+ CTL clone and the DRB30301-restricted H-Y-specific CD4+ helper T-cell clone that we earlier described were used to investigate the anti-leukemia efficacy of CD8+ and CD4+ T cells in NOD/scid mice. Results In vitro, the CD8+ H-Y specific CTL clone was highly cytotoxic against the ALL-CM leukemia. The H-Y specific CD4+ helper T-cell clone did not lyse the leukemia, but produced IFN-γ upon recognition. Infusion of the H-Y-specific CD8+ CTL clone (25×106 cells/mouse) 3 days after ALL-CM leukemia challenge significantly delayed leukemia progression by 3 weeks compared to a CMV-specific CD8+ CTL control clone (p<0,001). Despite no measurable in vitro cytotoxicity, the H-Y-specific CD4+ helper T-cell clone (25×106 cells/mouse) delayed leukemia progression by 2 weeks compared to a leukemia non-reactive HLA-DR1-specific CD4+ helper T-cell control clone (p<0,001). In vitro co-incubation of the H-Y-specific CD4+ helper T-cell clone did not influence leukemia proliferation but induced up-regulation of MHC-class I and II, CD80, CD86 and CD40. In vitro, pre-incubation of leukemia cells with the H-Y-specific CD4+ helper T-cell clone irradiated did not improve the in vivo anti-leukemia efficacy of the H-Y-specific CD8+ CTL clone. Co-infusion of the H-Y specific CD4+ helper T-cell clone did not augment the in vivo persistence of the H-Y-specific CD8+ CTL T-cell clone. Nevertheless, the co-infusion resulted in a delay in leukemia progression of approximately 5 weeks, suggesting an additive, non overlapping anti-leukemia mechanism. Conclusions Minor Hag-specific human CD4+ T lymphocytes may contribute to the GvL effect through a direct, non cytotoxic mechanism, which could be additive to that of CD8+ CTL. The nature of this non cytotoxic GvL effect is currently under investigation. A.B. and L.H. equally contributed to this study. Disclosures: No relevant conflicts of interest to declare.

Effect of an autoreactive T cell clone from (NZB × NZW)F1 mice on the production of anti-DNA antibodies in vivo and in vitro

1988 ◽  
Vol 18 (4) ◽  
pp. 281-287 ◽  
Author(s):  
Mitsuru Naiki ◽  
Yasuyuki Imai ◽  
Yuhsuke Kamita ◽  
Toshiaki Osawa
Keyword(s):  
T Cell ◽  
Cell Clone ◽  
Autoreactive T Cell ◽  
T Cell Clone ◽  
Dna Antibodies

scholarly journals Multiple discrete encephalitogenic epitopes of the autoantigen myelin basic protein include a determinant for I-E class II-restricted T cells.

1988 ◽  
Vol 168 (3) ◽  
pp. 1181-1186 ◽  
Author(s):  
S S Zamvil ◽  
D J Mitchell ◽  
M B Powell ◽  
K Sakai ◽  
J B Rothbard ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Cell Clone ◽  
Class Ii ◽  
T Cell Epitopes ◽  
Intact Mouse ◽  
T Cell Clone

Immunization with the autoantigen myelin basic protein (MBP) causes experimental allergic encephalomyelitis (EAE). Initial investigations indicated that encephalitogenic murine determinants of MBP were located only within MBP 1-37 and MBP 89-169. Encephalitogenic T cell epitopes within these fragments have been identified. Each epitope is recognized by T cells in association with separate allelic I-A molecules. A hybrid I-E-restricted T cell clone that recognizes intact mouse (self) MBP has been examined. The epitope recognized by this clone includes MBP residues 35-47. When tested in vivo, p35-47 causes EAE. T cell recognition of p35-47 occurs only in association with I-E molecules. These results provide the first clear example that antigen-specific T cells restricted by I-E class II molecules participate in murine autoimmune disease. Furthermore, it is clear that there are multiple (at least three) discrete encephalitogenic T cell epitopes of this autoantigen, each recognized in association with separate allelic class II molecules. These results may be relevant to human autoimmune diseases whose susceptibility is associated with more than one HLA-D molecule.

A “non-fratricidal” αβ- T Cell Receptor That Targets Survivin Expressed By Hematological Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 141-141
Author(s):  
Caroline Arber ◽  
Xiang Feng ◽  
Harshal Abhyankar ◽  
Helen E. Heslop ◽  
Malcolm K. Brenner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Hematological Malignancies ◽  
Cell Clone ◽  
Cell Receptor ◽  
Activated T Cells ◽  
T Cell Clone ◽  
Myeloid Leukemias

Abstract Survivin is broadly expressed by hematological malignancies as well as by solid tumors and may be a suitable target for T-cell immunotherapy. Previously, the utility of this target has been challenged by the occurrence of “fratricide” when T cells expressing a high avidity survivin-specific T cell receptor (TCR) killed each other because survivin epitopes can be presented by the T cells themselves (Leisegang M et al, J Clin Invest. 2010 Nov;120(11):3869-77). To overcome this obstacle, we used limiting dilution to isolate a new T-cell clone targeting the HLA-A*02-restricted survivin epitope ELT (survivin95-104) and its variant LML (survivin96-10497M) starting from autologous cultures, rather than from the allogeneic cultures previously used for this approach. In 51Chromium (Cr)-release assays, this T-cell clone, with nanomolar avidity, displayed specific killing against the survivin+HLA-A*02+ leukemia cells BV173 (39±16% specific lysis, E:T 40:1) and multiple myeloma cells U266 (20±7%) but not against HLA-A*02– HL-60 cells (2±2%). Furthermore, the colony formation of primary myeloid leukemias was inhibited (>50% reduction) while that of healthy bone marrow (BM) was unaffected. The TCR α- and β-chains were then cloned in an optimized retroviral vector that was used to transduce CD8+ T cells which then efficiently expressed the transgenic αβTCR (89±4%, n=6). As compared to non-transduced (NT) T cells, survivin-αβTCR+ T cells produced significant lysis of BV173 (46±14% vs 8±6%, E:T 20:1, n=12, p<0.001) and U266 (27±12% vs 14±6%, p=0.003) but not of HL-60 (14±7 vs 14±6 %, p=NS). Blocking the target cells with specific anti-MHC class I antibodies confirmed the HLA-restriction of TCR transgenic T cells. Importantly, transgenic cells recapitulated the function of the original clone by inhibiting colony formation (range 32-78% reduction, n=5) of primary myeloid leukemias while preserving normal clonogenic capacity of healthy BM or cord blood (n=5). When tested in vivo in a xenograft model of established systemic acute leukemia (FFLuc+BV173) using bioluminescent imaging, leukemia progression was significantly slower in mice treated with survivin-αβTCR+ versus NT T cells (40x106 ± 71x106 vs. 128 x 106 ± 176 x 106 photons/sec by day 28) (p=0.04) and survival improved (n=12/group, p=0.01). This effect was even more pronounced when T cells were transferred to mice with limited leukemia burden (bioluminescent signal by day 40: 8.1 x 106 ± 9 x 106 vs. 195 x 106 ± 85 x 106 photons/sec) (p=0.003, n=10/group). Overall survival was improved by day 80 (p<0.001) and 3/10 mice treated with TCR+ T cells completely cleared the leukemia. Crucially, the TCR cloned from our autologous culture system produced no fratricidal activity in 51Cr-release assays against HLA-A*02+ activated T cells (1±2%, E:T 20:1, n=7). Activated T cells were only killed by TCR+ T cells when they were also pulsed with survivin peptides (46±12% for LML, 68±14% for ELT, n=7). To elucidate at the molecular level why our “autologous” TCR had selective antitumor activity unlike the fratricidal activity of “allogeneic” TCRs (Leisegang M et al, J Clin Invest. 2010 Nov;120(11):3869-77), we modeled the structure of each TCR-peptide-HLA ternary complex using the Rosetta software. While the overall binding energies of TCR-peptide-HLA interfaces for both TCRs were similar, the “autologous” TCR showed a 48% higher binding energy contribution for the peptide as compared to the fratricidal TCR, whose interaction was primarily with the HLA molecule rather than with the survivin peptide in the HLA-binding groove. In conclusion, we have cloned a novel survivin-TCR with a highly epitope-specific binding mode that can be efficiently expressed in polyclonal T cells and provides antitumor activity in vitro and in vivo without affecting the survival of T cells or normal hematopoietic progenitors. Our results indicate that maximal recognition of the peptide presented in the HLA groove is critical for TCR selectivity. Disclosures: Heslop: Celgene: Patents & Royalties; Cell Medica: Patents & Royalties. Brenner:Celgene: Patents & Royalties, Research Funding. Dotti:Celgene: Patents & Royalties, Research Funding. Savoldo:Celgene: Patents & Royalties, Research Funding.

TIRC7 and HLA-DR axis contributes to inflammation in multiple sclerosis

2014 ◽  
Vol 20 (9) ◽  
pp. 1171-1181 ◽  
Author(s):  
JM Frischer ◽  
M Reindl ◽  
B Künz ◽  
T Berger ◽  
S Schmidt ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Cell Clone ◽  
Ex Vivo ◽  
Peripheral Blood Lymphocytes ◽  
Cytokine Expression ◽  
Hla Dr ◽  
T Cell Clone

Background and objective: Interactions between TIRC7 (a novel seven-transmembrane receptor on activated lymphocytes) and its ligand HLA-DR might be involved in the inflammatory process in multiple sclerosis (MS). Methods: Methods comprised immunohistochemistry and microscopy on archival MS autopsies, proliferation-, cytokine-, and surface-staining assays using peripheral blood lymphocytes (PBLs) from MS patients and an in vitro model. Results: TIRC7 was expressed in brain-infiltrating lymphocytes and strongly correlated with disease activity in MS. TIRC7 expression was reduced in T cells and induced in B cells in PBLs obtained from MS patients. After ex vivo activation, T cell expression of TIRC7 was restored in patients with active MS disease. The interaction of TIRC7+ T lymphocytes with cells expressing HLA-DR on their surface led to T cell proliferation and activation whereas an anti-TIRC7 mAb preventing interactions with its ligand inhibited proliferation and Th1 and Th17 cytokine expression in T cells obtained from MS patients and in myelin basic protein-specific T cell clone. Conclusion: Our findings suggest that TIRC7 is involved in inflammation in MS and anti-TIRC7 mAb can prevent immune activation via selective inhibition of Th1- and Th17-associated cytokine expression. This targeting approach may become a novel treatment option for MS.

CD8 T cells are not required for islet destruction induced by a CD4+ islet-specific T-cell clone

Diabetes ◽  
1992 ◽  
Vol 41 (12) ◽  
pp. 1603-1608 ◽  
Author(s):  
B. J. Bradley ◽  
K. Haskins ◽  
F. G. La Rosa ◽  
K. J. Lafferty
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Clone ◽  
T Cell Clone

γδ T cells for immune therapy of patients with lymphoid malignancies

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 200-206 ◽  
Author(s):  
Martin Wilhelm ◽  
Volker Kunzmann ◽  
Susanne Eckstein ◽  
Peter Reimer ◽  
Florian Weissinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Low Dose ◽  
Γδ T Cells ◽  
Low Grade ◽  
Treatment Schedule ◽  
Γδ T Cell

Abstract There is increasing evidence that γδ T cells have potent innate antitumor activity. We described previously that synthetic aminobisphosphonates are potent γδ T cell stimulatory compounds that induce cytokine secretion (ie, interferon γ [IFN-γ]) and cell-mediated cytotoxicity against lymphoma and myeloma cell lines in vitro. To evaluate the antitumor activity of γδ T cells in vivo, we initiated a pilot study of low-dose interleukin 2 (IL-2) in combination with pamidronate in 19 patients with relapsed/refractory low-grade non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). The objectives of this trial were to determine toxicity, the most effective dose for in vivo activation/proliferation of γδ T cells, and antilymphoma efficacy of the combination of pamidronate and IL-2. The first 10 patients (cohort A) who entered the study received 90 mg pamidronate intravenously on day 1 followed by increasing dose levels of continuous 24-hour intravenous (IV) infusions of IL-2 (0.25 to 3 × 106 IU/m2) from day 3 to day 8. Even at the highest IL-2 dose level in vivo, γδ T-cell activation/proliferation and response to treatment were disappointing with only 1 patient achieving stable disease. Therefore, the next 9 patients were selected by positive in vitro proliferation of γδ T cells in response to pamidronate/IL-2 and received a modified treatment schedule (6-hour bolus IV IL-2 infusions from day 1-6). In this patient group (cohort B), significant in vivo activation/proliferation of γδ T cells was observed in 5 patients (55%), and objective responses (PR) were achieved in 3 patients (33%). Only patients with significant in vivo proliferation of γδ T cells responded to treatment, indicating that γδ T cells might contribute to this antilymphoma effect. Overall, administration of pamidronate and low-dose IL-2 was well tolerated. In conclusion, this clinical trial demonstrates, for the first time, that γδ T-cell–mediated immunotherapy is feasible and can induce objective tumor responses. (Blood. 2003;102:200-206)

scholarly journals T Cell Activity Correlates with Oligomeric Peptide-Major Histocompatibility Complex Binding on T Cell Surface

2001 ◽  
Vol 276 (50) ◽  
pp. 47320-47328 ◽  
Author(s):  
Jennifer Buslepp ◽  
Rui Zhao ◽  
Debora Donnini ◽  
Douglas Loftus ◽  
Mohamed Saad ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Clone ◽  
Cell Activity ◽  
Class I ◽  
Antigenic Peptides ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
T Cell Clone

Recognition of virally infected cells by CD8+T cells requires differentiation between self and nonself peptide-class I major histocompatibility complexes (pMHC). Recognition of foreign pMHC by host T cells is a major factor in the rejection of transplanted organs from the same species (allotransplant) or different species (xenotransplant). AHIII12.2 is a murine T cell clone that recognizes the xenogeneic (human) class I MHC HLA-A2.1 molecule (A2) and the syngeneic murine class I MHC H-2 Dbmolecule (Db). Recognition of both A2 and Dbare peptide-dependent, and the sequences of the peptides recognized have been determined. Alterations in the antigenic peptides bound to A2 cause large changes in AHIII12.2 T cell responsiveness. Crystal structures of three representative peptides (agonist, null, and antagonist) bound to A2 partially explain the changes in AHIII12.2 responsiveness. Using class I pMHC octamers, a strong correlation is seen between T cell activity and the affinity of pMHC complexes for the T cell receptor. However, contrary to previous studies, we see similar half-lives for the pMHC multimers bound to the AHIII12.2 cell surface.

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