scholarly journals Influences of antigen processing on the expression of the T cell repertoire. Evidence for MHC-specific hindering structures on the products of processing.

1988 ◽  
Vol 168 (1) ◽  
pp. 357-373 ◽  
Author(s):  
S J Brett ◽  
K B Cease ◽  
J A Berzofsky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Processing ◽  
Sperm Whale ◽  
T Cell Response ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Similar Dose ◽  
Sperm Whale Myoglobin

Two lines of evidence in the current study indicate that antigen processing is a major factor, in addition to MHC binding and T cell repertoire, that determines Ir gene responsiveness and epitope immunodominance. First, immunization with synthetic peptides of myoglobin sequences revealed new reactivities that had not appeared after priming with native myoglobin. For example, B10.S mice (H-2S) immune to equine myoglobin predominantly responded to peptide 102-118, whereas there was little, if any, response to this peptide in B10.BR (H-2k) mice immunized with native equine myoglobin. However, after immunization with the 102-118 peptide, both strains responded to the peptide. After in vitro restimulation, B10.BR T cells responded as well as B10.S T cells. Similarly, some individual 102-118-specific T cell clones from mice of both haplotypes showed similar dose responses and fine specificity patterns. Thus, low responsiveness to this site is due neither to a hole in the repertoire nor to a failure to bind to the appropriate MHC molecule. An alternative explanation was suggested by the observation that, whereas B10.S T cells from peptide 102-118-immune mice responded almost as well to whole myoglobin as to the peptide, the B10.BR T cells from peptide immune mice, while responding well to peptide, were poorly stimulated by whole myoglobin. Thus, the product of natural processing of equine myoglobin probably has hindering structures in the regions flanking the core epitope 102-118 that interfere with presentation by I-Ak but not I-AS. The second line of evidence that processing of native myoglobin may influence the apparent specificity of the T cell response was obtained using the I-Ad-restricted sperm whale myoglobin 102-118-specific clone 9.27. This clone discriminated readily between whole sperm whale myoglobin and equine myoglobin, but it did not distinguish between peptides corresponding to 102-118 of the sperm whale and equine sequences. This distinction between equine peptide and native equine myoglobin could be overcome by artificial "processing" of equine myoglobin with cyanogen bromide. In both sets of experiments, F1 APCs that present the same epitope well to T cells of another haplotype failed to overcome the defect, which was therefore not due to the availability of different processed cleavage fragments in APC of different haplotypes, as would be expected if there were MHC-linked processing. Thus, the differential responses to peptides versus native molecule for both I-Ad- and I-Ak-restricted clones appeared to depend on the restricting molecule used.(ABSTRACT TRUNCATED AT 400 WORDS)

Mapping T-Cell Peptide Epitopes on Activated Recombinant Factor VII (rFVIIa) Contributing to Inhibitor Antibody Response

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2295-2295
Author(s):  
Pedro Paz ◽  
Jens Schroeder ◽  
Prasad Mathew ◽  
Marion Hardtke ◽  
Fred Aswad
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
Epitope Mapping ◽  
T Cell Response ◽  
Factor Vii ◽  
Amino Acid Substitutions ◽  
T Cell Repertoire ◽  
Cell Repertoire

Abstract Bypassing agents such as activated recombinant factor VII (rFVIIa) are used to treat acute bleeding episodes in patients with hemophilia and inhibitors to coagulation factors VIII (FVIII) or IX. BAY 86-6150 is a modified rFVIIa protein with 6 amino acid substitutions in the rFVII molecule that prolong half-life and improve potency compared with the currently available rFVIIa. In a dose-escalation clinical study, 1 patient out of a cohort of 10 treated with 6.5 μg/kg BAY 86-6150 developed low-titer neutralizing antibodies that were detected after the third exposure. The patient's anti-BAY 86-6150 antibodies also cross-reacted with and neutralized wild-type FVIIa (WT-FVIIa) in vitro. T-cell epitope mapping was performed to identify BAY 86-6150 sequence(s) that may have contributed to the immunogenic response in the patient by measuring CD4+ T-cell response to individual 15-mer peptides spanning BAY 86-6150. The epitope mapping study did not identify any of the 14 peptides unique to BAY 86-6150 as epitopes recognized by the patient's T cells. However, strong responses were detected against 2 WT-FVIIa peptides, WT p6-20 (EELRPGSLERECKEE) and WT p156-170 (GKVCPKGECPWQVLL), indicating that CD4+ T helper cells recognizing these WT peptides may have contributed to the immune response that resulted in the production of anti-BAY 86-6150 antibodies during treatment. It should be noted that although the patient had no detectable anti-FVIIa antibodies before the start of the study, he had been treated with factor eight inhibitor bypassing activity (FEIBA), which contains active FVII, on 3 consecutive days 3 months before entry into the study. Hence it is possible that the patient had been primed for a response against FVIIa that was triggered by the subsequent exposure to BAY 86-6150. The fact that the patient's T cells only responded to WT-FVIIa peptides might be explained if the WT-FVIIa peptides were seen as foreign/non-self peptides by his T-cell repertoire. Unfortunately, the patient's FVII gene sequence was not obtainable, and this possibility remains unanswered. The Universal Protein Resource (UniProt) database reports 2 natural FVII gene variants that encompass the WT p6-20 sequence (Millar, et al. Hum Genet. 2000;107:327-42; Herrmann, et al. Haemophilia. 2009;15:267-280) and one for the WT p156-170 sequence (Wulff and Herrmann. Hum Mutat. 2000;15:489-496) that resulted from single amino acid substitutions. Hence the possibility exists that the patient's T-cell repertoire sees WT-FVIIa sequences as foreign and immunogenic. T cells from 40 healthy donors were also tested for reactivity against the peptide panel to assess relative immunogenicity of BAY 86-6150 vs WT-FVIIa. Seven BAY 86-6150 neoepitopes were stimulatory for 8 unrelated healthy donor T cells, but their mean stimulation indices were not statistically higher than those observed against WT FVIIa peptides. Mean % stimulation values of the positive responses against the 7 BAY 86-6150 neoepitopes versus 39 WT FVIIa peptides were 1.09 (N=13 responses) vs 1.01 (N=70 responses; P=0.5059). Statistical analysis of the in vitro T-cell response indicates that specific mutations to BAY 86-6150 do not result in BAY 86-6150 being more immunogenic than WT FVIIa. This would suggest that BAY 86-6150 will not elicit stronger or higher frequency of anti-FVIIa antibody response than WT FVIIa in patients with hemophilia. Disclosures Paz: Bayer HealthCare: Employment. Schroeder:Bayer Pharma AG: Employment. Mathew:Bayer HealthCare Pharmaceuticals: Employment. Hardtke:Bayer Pharma AG: Employment. Aswad:Bayer HealthCare: Employment.

Impact of clonal competition for peptide-MHC complexes on the CD8+ T-cell repertoire selection in a persistent viral infection

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4283-4292 ◽  
Author(s):  
Katherine K. Wynn ◽  
Zara Fulton ◽  
Leanne Cooper ◽  
Sharon L. Silins ◽  
Stephanie Gras ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
Cd8 T Cell ◽  
Structural Features ◽  
T Cell Response ◽  
Helical Conformation ◽  
T Cell Repertoire ◽  
Cell Repertoire

AbstractCD8+ T-cell responses to persistent viral infections are characterized by the accumulation of an oligoclonal T-cell repertoire and a reduction in the naive T-cell pool. However, the precise mechanism for this phenomenon remains elusive. Here we show that human cytomegalovirus (HCMV)–specific CD8+ T cells recognizing distinct epitopes from the pp65 protein and restricted through an identical HLA class I allele (HLA B*3508) exhibited either a highly conserved public T-cell repertoire or a private, diverse T-cell response, which was uniquely altered in each donor following in vitro antigen exposure. Selection of a public T-cell receptor (TCR) was coincident with an atypical major histocompatibility complex (MHC)–peptide structure, in that the epitope adopted a helical conformation that bulged from the peptide-binding groove, while a diverse TCR profile was observed in response to the epitope that formed a flatter, more “featureless” landscape. Clonotypes with biased TCR usage demonstrated more efficient recognition of virus-infected cells, a greater CD8 dependency, and were more terminally differentiated in their phenotype when compared with the T cells expressing diverse TCR. These findings provide new insights into our understanding on how the biology of antigen presentation in addition to the structural features of the pMHC-I might shape the T-cell repertoire and its phenotype.

scholarly journals 762 A combination of functional biomarkers improves identification of the tumor-specific reactive T cell repertoire

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A810-A810
Author(s):  
Arianna Draghi ◽  
Katja Harbst ◽  
Inge Svane ◽  
Marco Donia
Keyword(s):  
T Cells ◽  
T Cell ◽  
De Novo ◽  
Autologous Tumor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Simple Method ◽  
Functional Biomarkers

BackgroundDetecting the entire repertoire of tumor-specific reactive T cells is essential for investigating the broad range of T cell functions in the tumor-microenvironment. At present, assays identifying tumor-specific functional activation measure either upregulation of specific surface molecules, de novo production of the most common antitumor cytokines or mobilization of cytotoxic granules.MethodsIn this study, we combined transcriptomic analyses of tumor-specific reactive tumorinfiltrating lymphocytes (TILs), TIL-autologous tumor cell co-cultures and commonly used established detection protocols to develop an intracellular flow cytometry staining method encompassing simultaneous detection of intracellular CD137, de novo production of TNF and IFNy and extracellular mobilization of CD107a.ResultsThis approach enabled the identification of a larger fraction of tumor-specific reactive T cells in vitro compared to standard methods, revealing the existence of multiple distinct functional clusters of tumor-specific reactive TILs. Publicly available datasets of fresh tumor single-cell RNA-sequencing from four cancer types were investigated to confirm that these functional biomarkers identified distinct functional clusters forming the entire repertoire of tumor-specific reactive T cells in situ.ConclusionsIn conclusion, we describe a simple method using a combination of functional biomarkers that improves identification of the tumor-specific reactive T cell repertoire in vitro and in situ.

Patients (Pts) Surviving Haploidentical Stem Cell Transplantation (SCT) after Ex Vivo Costimulatory Blockade To Induce Anergy Experience Few Long-Term Complications.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 599-599 ◽  
Author(s):  
Eva C. Guinan ◽  
John G. Gribben ◽  
Lisa L. Brennan ◽  
Lee M. Nadler
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Ex Vivo ◽  
Chronic Gvhd ◽  
T Cell Response ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Costimulatory Blockade ◽  
Cell Counts

Abstract Poor and delayed immune reconstitution remains a major stumbling block to successful SCT especially when alternative donors are used. Strategies to selectively remove or inactivate alloreactive cells while leaving the other donor T cell repertoire intact might address this problem. A functional T cell response requires an antigen (Ag)-specific MHC-restricted signal (signal 1) to the T cell receptor (TCR) by an Ag presenting cell (APC) as well as a second, Ag independent costimulatory signal (signal 2) provided in large part by B7 family members on APC to CD28 on T cells. Without signal 2, T cells develop tolerance to the specific Ag. Costimulation can be blocked by either CTLA4-Ig, a fusion of Ig with human CTLA4 (the T cell high affinity B7 ligand) or a combination of humanized IgG2 isotype mutated monoclonal antibodies to the APC molecules B7-1 and B7-2. In 2 pilot studies of patients (pts) undergoing haploidentical SCT, donor T cell replete BM was incubated ex vivo with recipient irradiated peripheral blood mononuclear cells with CTLA4-Ig (pilot 1) or anti-B7-1+anti-B7-2 (pilot 2) to induce alloAg specific tolerance. 19 pts age 7 mos-50 yrs (median 15 yrs) were enrolled on pilot 1 and 5 aged 4–12 (median 6) on pilot 2. 3 pts had congenital BM failure. 21 pts with malignancy, ALL (11), AML(7), NHL(2), MDS(1), were >CR1and 14/21 had progressive disease (PD). Pts received TBI based ablative conditioning. Pts received a median of 3.3x106/kg CD34+ cells (0.5–12.3) containing a median of 2.8x 107/kg CD3+ (0.7–6.8), 1.6x 107/kg CD4+ (0.4–4.1), and 1x107/kg CD8+ (0.2–3.7) T cells. One pt got additional anergized cells for slow recovery and engrafted fully. One AML pt had autologous persistence and graft failure (GF). Evaluable pts engrafted at median 21 d (range, 13–29) with full donor chimerism. Of the 21 evaluable pts, 9 (43%) had findings consistent with acute GVHD graded B (n=4), C (n=4) and D (n=1) despite inconsistent pathology. GVHD symptoms were largely isolated to the GI tract and resolved with observation or moderate steroids. No death was attributable to GVHD. 11 pts died early of a combination of bacterial or fungal infection and/or regimen-related toxicity at a median of 35 d (8–159). Of the remaining 13 pts, the GF pt died after 2nd SCT elsewhere, 1 pt had sudden death d 176 at home and 2 pts with extramedullary AML died d 60 and 149 with PD. One T-ALL pt died of late PD d 1758. All BM failure and 3/14 transplanted with PD survive. All 8 survivors (8/19 < 23 yrs) have 100% performance status at a median of 2423 d (1580–2875). None take medications or have chronic GVHD. 3 pts became CMV Ag + by d 100, (1 was transplanted with CMV), and responded to anti-viral therapy. Unlike many reported approaches to haploidentical SCT, aside from several CVL associated bacteremias, there have been no admissions for opportunistic infection and no late viral infections. All pts have good T cell counts, respond to vaccines and specific Ags and have good immunoglobulin levels. Costimulatory blockade, a method of limiting alloreactivity which leaves the remaining T cell repertoire intact, holds out promise as a method of overcoming alloreactivity while better preserving donor immune function and preserving anti-tumor activity. A new study combining costimulatory blockade and megadose stem cell SCT has been initiated.

Spectratype Analysis of In Vitro Donor Anti-Host T Cell Repertoire Responses Predict Those of In Vivo Post-BMT.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2163-2163
Author(s):  
Thea M. Friedman ◽  
Kira Goldgirsh ◽  
Jenny Zilberberg ◽  
Stephanie A. Berger ◽  
Joanne Filicko-O’Hara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Post Transplant ◽  
Cell Responses ◽  
Repertoire Analysis ◽  
Alloreactive T Cell

Abstract Immunotherapeutic strategies have gained recognition as viable alternatives to more conventional modalities for the treatment of cancer. In this regard, adoptive T cell therapy through allogeneic blood and marrow transplantation (BMT) has provided the strongest evidence that anti-tumor effects could be achieved against hematological malignancies. However, the major complications of BMT still include graft failure, opportunistic infections, disease relapse and graft-versus-host disease (GVHD). The presence of mature donor T cells in the transplant inoculum reduces the incidence of the first three complications, while unfortunately increasing the risk of GVHD, which can be directed against either HLA or minor histocompatibilty antigen (miHA) disparities. Thus, a major objective in the field has been to develop tactics that could facilitate the separation of graft-versus-tumor (GVT) effects from the deleterious effects of GVHD. One such approach would be to selectively deplete donor alloreactive T cells in the donor inoculum while allowing residual T cells to provide some protection against infection and to support a tumor-specific GVT response. For a more targeted approach, delayed donor lymphocyte infusion (DLI) of positively-selected donor GVT-reactive T cells could be used weeks to months post-transplant, if these elements were identifiable. In this regard, TCR Vβ repertoire analysis by CDR3-size spectratyping can be a powerful tool for the characterization of alloreactive T cell responses. Theoretically, molecular analysis of T cell responses in vitro, given the high sensitivity of the PCR-based spectratyping technique, should identify the most potentially critical Vβ families involved in the later development of GVHD and GVT effects in patients. To this end, we tested the hypothesis that T cell repertoire analysis of HLA-matched sibling (SIB) or matched unrelated donors (URD) from in vitro, host-stimulated, mixed lymphocyte cultures (MLC) would be predictive of the TCR-Vβ spectratype analysis of the T cell repertoire in the patient following BMT. In this study, we examined 17 patient pairs and report that for the resolvable Vβ families, we observed overall 71.2 ± 11.9% (mean ± SD.; range 40%–85%) of the in vitro anti-host T cell responses were predictive of those in the patient post-transplant. Of the 28.8% non-predictive Vβ families, 6.9 ± 6.3% (range 0%–27%) exhibited skewing in the MLC but no skewing in the patient post-transplant repertoire, 9.3 ± 6.3% (range 0%–18.8%) exhibited skewing in different peaks within the same Vβ family, and 12.5 ± 10.8% (range 0%–40%) showed skewing in the patient post-transplant and none in the MLC. Taken together, these results suggest that the in vitro MLC T cell responses show good consistency with post-transplant patient responses. Thus, in vitro spectratyping may be useful for predicting the alloreactive T cell responses involved in GVHD and could be used to guide custom-designed select Vβ family T cell-depleted transplants to improve patient outcomes. The additional advantage of this approach is that minimization of GVHD risk can be obtained without any direct knowledge of the specific miHA involved in the individual donor-patient pair.

Characterization of the T-cell repertoire in autologous graft-versus-host disease (GVHD): evidence for the involvement of antigen-driven T-cell response in the development of autologous GVHD

Blood ◽  
2001 ◽  
Vol 98 (3) ◽  
pp. 868-876 ◽  
Author(s):  
Yuji Miura ◽  
Christopher J. Thoburn ◽  
Emilie C. Bright ◽  
Matthias Sommer ◽  
Susan Lefell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Cell Response ◽  
Effector T Cells ◽  
T Cell Response ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Graft Versus Host

Abstract Administration of cyclosporine A (CsA) after autologous stem cell transplantation elicits an autoimmune syndrome with pathology similar to graft-versus-host disease (GVHD). This syndrome, termed autologous GVHD, is associated with the appearance of autoreactive T cells directed at major histocompatibility class (MHC) class II antigens. In the rat model of autologous GVHD, clonal analysis reveals that the effector T cells are highly conserved and recognize a peptide from the invariant chain peptide presented by MHC class II. Although human autologous GVHD effector T cells share a similar phenotypic specificity, clonality of the response in humans has not been determined. To examine the human effector T-cell response, the T-cell repertoire of peripheral blood lymphocytes was assessed by complementarity-determining region 3 (CDR3) size distribution analysis and T-cell clonotype analysis in 26 patients treated with CsA after transplantation. Autologous GVHD developed in 3 of 4 patients with human leukocyte antigen (HLA)-DRB1*0701, and clonal expansions of β-chain variable region (BV)16+ T cells were shared. Clonal expansions within BV15+ and BV22+ T cells were also detected in 4 of 6 patients with HLA-DRB1*1501 and in 3 of 4 patients with HLA-DRB1*0401, respectively. Sequencing of BV16 cDNA for which the CDR3 size pattern exhibited apparent clone predominance revealed an identical CDR3 peptide sequence in 2 different patients, one with HLA-DRB1*0701 and the other with HLA-DRB1*1502. These findings indicate that the discrete antigen-driven expansion of T cells is involved in autologous GVHD.

Binding of β2–glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1552-1557 ◽  
Author(s):  
Masataka Kuwana ◽  
Eiji Matsuura ◽  
Kazuko Kobayashi ◽  
Yuka Okazaki ◽  
Junichi Kaburaki ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Processing ◽  
T Cell Response ◽  
Autoimmune Response ◽  
Dependent Manner ◽  
Glycoprotein I ◽  
Autoreactive T Cell

Abstract Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder in association with autoantibodies to phospholipid (PL)–binding plasma proteins, such as β2-glycoprotein I (β2GPI). We have recently found that CD4+ T cells autoreactive to β2GPI in patients with APS preferentially recognize a cryptic peptide encompassing amino acid residues 276-290 (p276-290), which contains the major PL-binding site, in the context of DR53. However, it is not clear how previously cryptic p276-290 becomes visible to the immune system and elicits a pathogenics autoimmune response to β2GPI. Here we show that presentation of a disease-relevant cryptic T-cell determinant in β2GPI is induced as a direct consequence of antigen processing from β2GPI bound to anionic PL. Dendritic cells or macrophages pulsed with PL-bound β2GPI induced a response of p276-290–specific CD4+ T-cell lines generated from the patients in an HLA-DR–restricted and antigen-processing–dependent manner but those with β2GPI or PL alone did not. In addition, the p276-290–reactive T-cell response was primed by stimulating peripheral blood T cells from DR53-carrying healthy individuals with dendritic cells bearing PL-bound β2GPI in vitro. Our finding is the first demonstration of an in vitro mechanism eliciting pathogenic autoreactive T-cell responses to β2GPI and should be useful in clarifying the pathogenesis of APS.

scholarly journals Unresponsiveness to a self-peptide of mouse lysozyme owing to hindrance of T cell receptor-major histocompatibility complex/peptide interaction caused by flanking epitopic residues.

1996 ◽  
Vol 183 (2) ◽  
pp. 535-546 ◽  
Author(s):  
K D Moudgil ◽  
I S Grewal ◽  
P E Jensen ◽  
E E Sercarz
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Response ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Histocompatibility Complex ◽  
Critical Residues ◽  
Mouse Lysozyme

A self-peptide containing amino acid residues 46-61 (NRGDQSTDYGIFQINSR) of mouse lysozyme (ML) (p46-61, which binds strongly to the A(k) molecule but does not bind to the E(k) molecule), can induce a strong proliferative T cell response in CBA/J mice (A[k], E[k]) but no response at all in B10.A(4R) and CBA/J mice. The critical residues within p46-59 are immunogenic in both B10.A(4R) and CBA/J mice. The critical residues within p46-61 reside between amino acid positions 51 and 59. T cells of B10.A(4R) mice primed with the truncated peptides in vivo cannot be restimulated by p46-61 in vitro. This suggests that T cell receptor (TCR) contact (epitopic) residue(s) flanking the minimal 51-59 determinant within p46-61 hinder the interaction of the p46-61/A(k) complex with the appropriate TCR(S), thereby causing a lack of proliferative T cell response in this mouse strain. Unlike B10.A(4R) mice, [B10.A(4R) x CBA/J]F1 mice responded vigorously to p46-61, suggesting that thymic APC of B10.A(4R) mice do not present a self ligand to T cells resulting in a p46-61-specific hole in the T cell repertoire in B10.A(4R) or the F1 mice. Moreover, APC from B10.A(4R) mice are capable of efficiently presenting p46-61 to peptide-specific T cell lines from CBA/J mice. The proliferative unresponsiveness of B10.A(4R) mice to p46-61 is not due to non-major histocompatibility complex genes because B10.A mice (A[k], E[k]) respond well to p46-61. Interestingly, B10.A(4R) mice can raise a good proliferative response to p46-61 (R61A) (in which the arginine residue at position 61 (R61L/F/N/K), indicating that R61 was indeed responsible for hindering the interaction of p46-61 with the appropriate TCR. Finally, chimeric mice [B10.A(4R)-->B10.A] responded vigorously to p46-61, suggesting that thymic antigen presentation environment of the B10.A mouse was critical for development of a p46-61-reactive T cell repertoire. Thus, we provide experimental demonstration of a novel mechanism for unresponsiveness to a self peptide, p46-61, in the B10.A(4R) mouse owing to hindrance: in this system it is the interaction between the available TCR and the A(k)/p46-61 complex, which is hindered by epitopic residue(s) within p46-61. We argue that besides possessing T cells that are hindered by R61 of p46-61, CBA/J and B10.A mice have developed an additional subset of T cells bearing TCRs which are not hinderable by R61, presumably through positive selection with peptides derived from class II E(k), or class I D(k)/D(d) molecules. These results have important implications in self tolerance, shaping of the T cell repertoire, and in defining susceptibility to autoimmunity.

scholarly journals The Cytomegalovirus-Specific CD4+ T-Cell Response Expands with Age and Markedly Alters the CD4+ T-Cell Repertoire

2007 ◽  
Vol 81 (14) ◽  
pp. 7759-7765 ◽  
Author(s):  
Batoul Pourgheysari ◽  
Naeem Khan ◽  
Donna Best ◽  
Rachel Bruton ◽  
Laxman Nayak ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Immune Response ◽  
T Cell Repertoire ◽  
Immune Senescence ◽  
Cell Repertoire

ABSTRACT Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8+ T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4+ T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4+ T-cell immune response increases from a mean of 2.2% of the CD4+ T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4+ T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4+ T-cell repertoire in healthy aged donors, including an increase in CD57+ expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4+ T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals.

Generation of T-cells reactive against CT-7 and BCMA peptides: Potential targets for T-cell immunotherapy of multiple myeloma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7615-7615
Author(s):  
L. D. Anderson ◽  
D. G. Maloney ◽  
S. R. Riddell
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Plasma Cell ◽  
Target Cells ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
T Cell Therapy

7615 Background: Multiple myeloma is a malignant plasma cell disorder that is incurable with chemotherapy or autologous stem cell transplantation (SCT), and novel therapies with lower toxicity are needed. There is evidence that T-cells can recognize myeloma and mediate anti-tumor effects, but the lack of defined target antigens other than idiotype has hindered the development of myeloma-specific T-cell therapy. We are investigating cancer-testis antigens and overexpressed “self”-proteins as candidate myeloma antigens, including MAGE-C1 (CT-7), which is expressed by >80% of myelomas, and B-Cell Maturation Antigen (BCMA), a plasma cell differentiation antigen commonly over-expressed in myeloma. Methods: To identify potential T-cell epitopes from CT-7 and BCMA, we scanned the protein sequences with computer algorithms and synthesized peptides predicted to bind to HLA-A2 and A3. CT-7 and BCMA are both “self” proteins to which the T-cell repertoire may be relatively tolerant, so we have utilized culture conditions that facilitate the expansion of rare myeloma-reactive T-cells. CD8+ T cells were stimulated in vitro with autologous dendritic cells pulsed with CT-7 or BCMA peptides in the presence of cytokines that avoid excessive nonspecific expansion of T-cells. Wells were screened for reactivity against peptide-pulsed target cells and myeloma cell lines. Results: A specific CD8+ T-cell response by both ELISPOT and cytotoxicity assays to at least one HLA-A2 peptide from each of the CT-7 and BCMA proteins has been identified in normal donors. CT-7 and BCMA-specific T-cells are being cloned in order to determine their ability to recognize primary myeloma cells. Experiments are also in progress to elicit responses to these peptides in myeloma patient samples and to screen HLA A3-binding epitopes. Conclusions: T-cells recognizing CT-7 and BCMA are detectable in the normal T-cell repertoire and can be isolated and expanded in vitro. We are currently pursuing the identification of additional antigenic epitopes in these proteins to define their potential utility as targets for vaccination or adoptive T-cell therapy. No significant financial relationships to disclose.

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