scholarly journals Antigen-specific T cell clones restricted to unique F(1) major histocompatibility complex determinants. Inhibition of proliferation with a monoclonal anti-Ia antibody

1981 ◽  
Vol 153 (3) ◽  
pp. 677-693 ◽  
Author(s):  
B Sredni ◽  
LA Matis ◽  
EA Lerner ◽  
WE Paul ◽  
RH Schwartz
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Proliferative Response ◽  
Cell Populations ◽  
Gene Products ◽  
Spleen Cells ◽  
Histocompatibility Complex ◽  
Cell Clones ◽  
Antigen Presenting

The existence of T cells specific for soluble antigens in association with unique F(1) or recombinant major histocompatibility complex (MHC) gene products was first postulated from studies on the proliferative response of whole T cell populations to the antigen poly(Glu(55)Lys(36)Phe(9))(n) (GLφ). In this paper we use the newly developed technology of T lymphocyte cloning to establish unequivocally the existence of such cells specific for GLφ and to generalize their existence by showing that F(1)- specific cells can be isolated from T cell populations primed to poly(Glu(60)Ala(30)Tyr(10))(n) (GAT) where such clones represent only a minor subpopulation of cells. Gl.4b-primed B10.A(5R) and GAT-primed (B10.A × B10)F(1) lymph node T cells were cloned in soft agar, and the colonies that developed were picked and expanded in liquid culture. The GLφ-specific T cells were then recloned under conditions of high-plating efficiency to ensure that the final colonies originated from single cells. T cells from such rigorously cloned populations responded to stimulation with GILφ but only in the presence of nonimmune, irradiated spleen cells bearing (B10.A × B10)F(1) or the syngeneic B 10.A(5R) recombinant MHC haplotype. Spleen cells from either the B10 or B 10.A parental strains failed to support a proliferative response, even when added together. (B10 × B10.D2)F(1) and (B10 × B10.RIII)F(1) spleen cells also supported a proliferative response but (B10 × B10.Q)F(1) and (B10 X B10.S)F(1) spleen cells did not. These results suggested that the T cell clones were specific for GL[phi} in association with the β(AE)(b)-α(E) (k,d,r,) Ia molecule and that recognition required both gene products to be expressed in the same antigen-presenting cells. Support for this interpretation was obtained from inhibition experiments using the monoclonal antibody Y-17 specific for a determinant on the β(AE)(b)-αE Ia molecule. Y-17 completely inhibited the proliferative response of a GLφ-specific clone but had no effect on the response of either a PPD-specific or GAT-specific clone, both of which required the β(A)-α(A) Ia molecule as their restriction element. No evidence could be found for the involvement of suppressor T cells in this inhibition. We therefore conclude that the phenomenon of F(1)-restricted recognition by proliferating T cells results from the presence of antigen- specific clones that must recognize unique F(1) or recombinant Ia molecules on the surface of antigen-presenting cells in addition to antigen in order to be stimulated.

scholarly journals Antigen presentation in the murine T-lymphocyte proliferative response. I. Requirement for genetic identity at the major histocompatibility complex

1977 ◽  
Vol 146 (3) ◽  
pp. 828-843 ◽  
Author(s):  
A Yano ◽  
RH Schwartz ◽  
WE Paul
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Lymphocytes ◽  
Antigen Presentation ◽  
T Lymphocyte ◽  
Proliferative Response ◽  
Gene Products ◽  
Major Histocompatibility ◽  
Spleen Cells ◽  
Histocompatibility Complex

A method is described for stimulating proliferation in primed populations of murine T lymphocytes using antigen bound to mitomycin-C-treated spleen cells. This form of antigen presentation appears to be an active process because heat-killed spleen cells are ineffective, and because genetic similarity at the major histocompatibility complex (MHC) between the responder T cells and the presenting spleen cells is required for effective interactions. At all times examined, from day 3 to day 6 of the proliferative response, syngeneic spleen cells presented antigen better to peritoneal exudate T-lymphocyte-enriched cells (PETLES) than semisyngeneic F(1) spleen cells, which in turn could present antigen better than totally allogeneic spleen cells. Spleen cell mixing experiments demonstrated that these genetic restrictions were not the result of suppression by the ongoing mixed lymphocyte reactions (MLR) in the allogeneic and F(1) cases. Furthermore, incompatibility at the Mls locus generated a strong MLR but failed to prevent antigen presentation if the spleen cells and PETLES were compatible. Genetic mapping studies demonstrated that compatibility at only the I-A subregion of the MHC was sufficient for effective presentation of the antigen, dinitrophenylated ovalbumin. Compatibility at only the K region, or the K and D regions was not sufficient. These results support the concept that functional activation of primed, proliferating T lymphocytes requires the participation of gene products coded for by the I region of the MHC. This conclusion is consistent with a growing body of evidence which suggests that most T cells recognize antigen in association with MHC gene products.

scholarly journals Indirect allorecognition of platelets by T helper cells during platelet transfusions correlates with anti-major histocompatibility complex antibody and cytotoxic T lymphocyte formation [published erratum appears in Blood 1995 Dec 15;86(12):4710]

Blood ◽  
1995 ◽  
Vol 86 (2) ◽  
pp. 805-812 ◽  
Author(s):  
JW Semple ◽  
ER Speck ◽  
YP Milev ◽  
V Blanchette ◽  
J Freedman
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class I ◽  
T Lymphocyte ◽  
Nk Cell ◽  
Cytotoxic T Lymphocyte ◽  
Spleen Cells ◽  
Histocompatibility Complex ◽  
Platelet Transfusions

To study the cellular immunology of platelet-induced alloimmunization, a murine transfusion model was developed. BALB/c (H-2d) recipient mice were transfused weekly with 2 x 10(8) platelets or 10(3) leukocytes from C57BL/6 (H-2b) donor mice. Recipient antidonor major histocompatibility complex (MHC) class I alloantibodies could be detected in flow cytometric assays by the fifth platelet transfusion. In contrast, when leukocytes only were transfused, alloantibodies were not detected. In vitro assays demonstrated that murine H-2b platelets were positive for MHC class I expression but lacked MHC class II molecules on their membranes and were unable to stimulate proliferation or cytokine production when incubated with naive H-2d spleen cells. In vivo, however, platelet transfusions induced two distinct patterns of cell-mediated reactivity. First, during the initial transfusions and before alloantibody formation, there was induction of T-cell anergy, characterized by the inability of recipient T cells to respond to Concanavalin A (ConA) or to proliferate in an antidonor mixed lymphocyte reaction (MLR), together with suppressed natural killer (NK) cell activity. This unresponsiveness was associated with a transient increase in nitric oxide (NO)-dependent cytotoxicity and interleukin-1 (IL-1) production. Second, once alloantibodies developed, significantly increased antidonor CD8+ cytotoxic T lymphocyte (CTL) and NK cell responses were observed. At this time, when recipient spleen cells were depleted of CD8+ T cells and incubated with only donor platelets in 7- day antigen-presenting cell (APC) assays, enhanced proliferation and IL- 2 production occurred. These cellular responses were not seen when 10(3) allogeneic leukocytes were transfused. Thus, the results suggest that leukoreduced platelet transfusions induce antidonor MHC antibodies and CD8+ CTL responses in recipient mice. At the same time, the transfusions induced recipient CD4+ T-cell activation when incubated with donor platelets in the presence of syngeneic APCs, an indirect recognition pathway that correlates with the time of alloantibody production.

scholarly journals Functional properties of T cell clones with a double specificity for alloantigens and foreign antigens.

1984 ◽  
Vol 160 (5) ◽  
pp. 1300-1315 ◽  
Author(s):  
S J Waters ◽  
P R Luzzatti ◽  
C A Bona
Keyword(s):  
Major Histocompatibility Complex ◽  
Lymph Node ◽  
T Cell ◽  
B Cells ◽  
Functional Properties ◽  
Proliferative Response ◽  
Keyhole Limpet Hemocyanin ◽  
Histocompatibility Complex ◽  
Cell Clones ◽  
Clonal Nature

Four keyhole limpet hemocyanin (KLH)-specific clones prepared from the lymph node of CB6F1 mice immunized with KLH had a proliferative response restricted to parental major histocompatibility complex (MHC)-encoded antigens. These clones provided help for CB6F1 trinitrophenyl-ovalbumin (TNP-OVA)-primed B cells to mount IgM and IgG plaque-forming cell (PFC) responses in the presence of KLH-TNP conjugate. In addition, two of these clones (A12.11 and F6) proliferated in response to allogeneic cells from mice strains bearing H-2k or H-2q haplotypes, respectively. However, they did not provide help for C3H/He or B10.Q primed B cells. The clonal nature of A12.11 and F6 was demonstrated by subcloning and in BUdR-suicide experiments. The proliferative response to KLH was ablated by anti-Iad antibodies, whereas the proliferation induced by C3H/HeJ stimulating cells was ablated by anti-Iak antibodies. Furthermore, both responses were inhibited by a monoclonal anti-clonotype (idiotype) antibody. Taken together, these results strongly support the hypothesis that the same receptor recognizes alloantigens and KLH associated with self-antigens.

scholarly journals Presentation of Toxoplasma gondii Antigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells

2007 ◽  
Vol 75 (11) ◽  
pp. 5200-5209 ◽  
Author(s):  
Florence Dzierszinski ◽  
Marion Pepper ◽  
Jason S. Stumhofer ◽  
David F. LaRosa ◽  
Emma H. Wilson ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Antigen Processing ◽  
Cell Types ◽  
T Cell Response ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Antigen Presenting

ABSTRACT Challenge with the intracellular protozoan parasite Toxoplasma gondii induces a potent CD8+ T-cell response that is required for resistance to infection, but many questions remain about the factors that regulate the presentation of major histocompatibility complex class I (MHC-I)-restricted parasite antigens and about the role of professional and nonprofessional accessory cells. In order to address these issues, transgenic parasites expressing ovalbumin (OVA), reagents that track OVA/MHC-I presentation, and OVA-specific CD8+ T cells were exploited to compare the abilities of different infected cell types to stimulate CD8+ T cells and to define the factors that contribute to antigen processing. These studies reveal that a variety of infected cell types, including hematopoietic and nonhematopoietic cells, are capable of activating an OVA-specific CD8+ T-cell hybridoma, and that this phenomenon is dependent on the transporter associated with antigen processing and requires live T. gondii. Several experimental approaches indicate that T-cell activation is a consequence of direct presentation by infected host cells rather than cross-presentation. Surprisingly, nonprofessional antigen-presenting cells (APCs) were at least as efficient as dendritic cells at activating this MHC-I-restricted response. Studies to assess whether these cells are involved in initiation of the CD8+ T-cell response to T. gondii in vivo show that chimeric mice expressing MHC-I only in nonhematopoietic compartments are able to activate OVA-specific CD8+ T cells upon challenge. These findings associate nonprofessional APCs with the initial activation of CD8+ T cells during toxoplasmosis.

scholarly journals Major Histocompatibility Complex Class II DR-Restricted Memory CD4+ T Lymphocytes Recognize Conserved Immunodominant Epitopes of Anaplasma marginale Major Surface Protein 1a

2002 ◽  
Vol 70 (10) ◽  
pp. 5521-5532 ◽  
Author(s):  
Wendy C. Brown ◽  
Travis C. McGuire ◽  
Waithaka Mwangi ◽  
Kimberly A. Kegerreis ◽  
Henriette Macmillan ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Protective Immunity ◽  
Surface Protein ◽  
T Cell Epitopes ◽  
Major Surface Protein ◽  
Histocompatibility Complex ◽  
Cell Clones ◽  
Major Surface

ABSTRACT Native major surface protein 1 (MSP1) of Anaplasma marginale, composed of covalently associated MSP1a and MSP1b proteins, stimulates protective immunity in cattle against homologous and heterologous strain challenge. Protective immunity against pathogens in the family Anaplasmataceae involves both CD4+ T cells and neutralizing immunoglobulin G. Thus, an effective vaccine should contain both CD4+ T- and B-lymphocyte epitopes that will elicit strong memory responses upon infection with homologous and heterologous strains. Previous studies demonstrated that the predominant CD4+ T-cell response in MSP1 vaccinates is directed against the MSP1a subunit. The present study was designed to identify conserved CD4+ T-cell epitopes in MSP1a presented by a broadly represented subset of major histocompatibility complex (MHC) class II molecules that would be suitable for inclusion in a recombinant vaccine. Transmembrane protein prediction analysis of MSP1a from the Virginia strain revealed a large hydrophilic domain (HD), extending from amino acids (aa) 1 to 366, and a hydrophobic region extending from aa 367 to 593. The N terminus (aa 1 to 67) includes one 28-aa form A repeat and one 29-aa form B repeat, which each contain an antibody neutralization-sensitive epitope [Q(E)ASTSS]. In MSP1 vaccinates, recombinant MSP1a HD (aa 1 to 366) stimulated recall proliferative responses that were comparable to those against whole MSP1a excluding the repeat region (aa 68 to 593). Peptide mapping determined a minimum of five conserved epitopes in aa 151 to 359 that stimulated CD4+ T cells from cattle expressing DR-DQ haplotypes common in Holstein-Friesian breeds. Peptides representing three epitopes (aa 231 to 266, aa 270 to 279, and aa 290 to 319) were stimulatory for CD4+ T-cell clones and restricted by DR. A DQ-restricted CD4+ T-cell epitope, present in the N-terminal form B repeat (VSSQSDQASTSSQLG), was also mapped using T-cell clones from one vaccinate. Although form B repeat-specific T cells did not recognize the form A repeat peptide (VSSQS_EASTSSQLG), induction of T-cell anergy by this peptide was ruled out. The presence of multiple CD4+ T-cell epitopes in the MSP1a HD, in addition to the neutralization-sensitive epitope, supports the testing of this immunogen for induction of protective immunity against A. marginale challenge.

scholarly journals T cells specific for alpha-beta interface regions of hemoglobin recognize the isolated subunit but not the tetramer and indicate presentation without processing

1989 ◽  
Vol 86 (17) ◽  
pp. 6729-6733 ◽  
Author(s):  
M Z Atassi ◽  
M Yoshioka ◽  
G S Bixler
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Cell Lines ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Oligomeric Protein ◽  
T Cell Lines ◽  
Antigen Presenting

Processing of a protein antigen into fragments is believed to be a prerequisite for its presentation by the antigen-presenting cell to the T cell. This model would predict that, in oligomeric proteins, T cells prepared with specificity for regions that are buried within subunit association surfaces should recognize the respective regions in vitro equally well on the isolated subunit or on the oligomer. Three hemoglobin (Hb) alpha-chain synthetic peptides, corresponding to areas that are situated either completely [alpha-(31-45)] or partially [alpha-(41-45) and alpha-(81-95)] within the interface between the alpha and beta subunits of Hb, and a fourth peptide representing a completely exposed area in tetrameric Hb were used as immunogens in SJL/J (H-2s) mice. Peptide-primed T cells were passaged in vitro with the respective peptide to obtain peptide-specific T-lymphocyte lines. T-cell clones were isolated from these lines by limiting dilution. T-cell lines and clones that were specific for buried regions in the subunit association surfaces recognized the free peptide and the isolated subunit but not the Hb tetramer. On the other hand, T cells with specificity against regions that are not involved in subunit interaction and are completely exposed in the tetramer recognized the peptide, the isolated subunit, and the oligomeric protein equally well. The responses of the T-cell lines and clones were major histocompatibility complex-restricted. Since the same x-irradiated antigen-presenting cells were employed, the results could not be attributed to differences or defects in Hb processing. The findings indicate that in vitro the native (unprocessed and undissociated) oligomeric protein was the trigger of major histocompatibility complex-restricted T-cell responses.

scholarly journals Murine gamma/delta-expressing T cells affect alloengraftment via the recognition of nonclassical major histocompatibility complex class Ib antigens

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4463-4472 ◽  
Author(s):  
BR Blazar ◽  
PA Taylor ◽  
JA Bluestone ◽  
DA Vallera
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Graft Rejection ◽  
Gene Products ◽  
Gamma Delta ◽  
Histocompatibility Complex ◽  
Alpha Beta ◽  
Delta Cells ◽  
Gamma Delta Cells

T cells with antidonor specificities have been isolated from human recipients experiencing graft rejection after allogeneic bone marrow transplantation (BMT). Partial T-cell depletion of unrelated BM grafts with an anti- T-cell receptor (TCR) monoclonal antibody (MoAb) directed against the TCR alpha/beta heterodimer have shown that the incidence of graft-versus-host disease is low and that the incidence of durable engraftment is high. These studies suggest either that the number of residual TCR alpha/beta+ cells was sufficient to permit alloengraftment or that the preservation of cells other than TCR alpha/beta+ cells was beneficial for engraftment. With respect to the latter, one such candidate cell is the TCR gamma/delta+ T cell. Because no studies have specifically examined whether TCR gamma/delta+ cells might be capable of eliminating BM-derived hematopoietic cells, we established a new graft rejection model system in which transgenic (Tg) H-2d mice (termed G8), known to express gamma/delta heterodimers on high proportion of peripheral T cells, were used as BMT recipients. These Tg TCR gamma/delta+ cells respond vigorously to target cells that express the nonclassical major histocompatibility complex (MHC) class lb region gene products encoded in H-2T region of H-2T(b)+ strains. G8 Tg mice were used as recipients for C57BL/6 (B6: H-2(b); H-2T(b)) T-cell- depleted (TCD) donor BM. We show that G8 Tg (H-2(d), H-2T(d)) mice are potent mediators of B6 BM graft rejection and that the rejection process was inhibited by anti-TCR gamma/delta MoAbs. In contrast, BM from a B6 congenic strain that expresses the H-2T(a) allele, B6.A- Tl(a)/BoyEg, was readily accepted, suggesting that H-2T antigens on repopulating donor BM cells are the targets of host graft rejecting T cells that express the TCR gamma/delta heterodimer. PB chimerism studies were performed at > or = 1.5 months post-BMT using TCD BM from severe combined immunodeficient allogeneic donors, which is highly susceptible to rejection by the host. The addition of donor G8 TCR gamma/delta+ cells to TCD donor BM was shown to significantly increase alloengraftment in B6 recipients. These results show that (1) host TCR gamma/delta+ cells can reject repopulating donor cells, presumably by responding to nonclassical MHC class lb gene products expressed on BM- derived hematopoietic progenitor cells; and (2) donor TCR gamma/delta+ cells can facilitate the alloengraftment of rigorously TCD donor BM.

scholarly journals Major Histocompatibility Complex–independent Recognition of a Distinctive Pollen Antigen, Most Likely a Carbohydrate, by Human CD8+ α/β T Cells

1997 ◽  
Vol 186 (6) ◽  
pp. 899-908 ◽  
Author(s):  
Silvia Corinti ◽  
Raffaele De Palma ◽  
Angelo Fontana ◽  
Maria Cristina Gagliardi ◽  
Carlo Pini ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Response ◽  
Major Histocompatibility ◽  
T Cell Clones ◽  
Histocompatibility Complex ◽  
Cell Clones

We have isolated CD8+ α/β T cells from the blood of atopic and healthy individuals which recognize a nonpeptide antigen present in an allergenic extract from Parietaria judaica pollen. This antigen appears to be a carbohydrate because it is resistant to proteinase K and alkaline digestion, is hydrophilic, and is sensitive to trifluoromethane-sulphonic and periodic acids. In addition, on a reverse-phase high performance liquid chromatography column the antigen recognized by CD8+ T cells separates in a fraction which contains >80% hexoses (glucose and galactose) and undetectable amounts of proteins. Presentation of this putative carbohydrate antigen (PjCHOAg) to CD8+ T cell clones is dependent on live antigen presenting cells (APCs) pulsed for >1 h at 37°C, suggesting that the antigen has to be internalized and possibly processed. Indeed, fixed APCs or APCs pulsed at 15°C were both unable to induce T cell response. Remarkably, PjCHOAg presentation is independent of the expression of classical major histocompatibility complex (MHC) molecules or CD1. CD8+ T cells stimulated by PjCHOAg-pulsed APCs undergo a sustained [Ca2+]i increase and downregulate their T cell antigen receptors (TCRs) in an antigen dose– and time-dependent fashion, similar to T cells stimulated by conventional ligands. Analysis of TCR Vβ transcripts shows that six independent PjCHOAg-specific T cell clones carry the Vβ8 segment with a conserved motif in the CDR3 region, indicating a structural requirement for recognition of this antigen. Finally, after activation, the CD8+ clones from the atopic patient express CD40L and produce high levels of interleukins 4 and 5, suggesting that the clones may have undergone a Th2-like polarization in vivo. These results reveal a new class of antigens which triggers T cells in an MHC-independent way, and these antigens appear to be carbohydrates. We suggest that this type of antigen may play a role in the immune response in vivo.

scholarly journals Antigen-reactive T clones. III. Low responder antigen-presenting cells function effectively to present antigen to selected T cell clones derived from (High Responder x Low Responder)F1 mice.

1981 ◽  
Vol 154 (3) ◽  
pp. 883-891 ◽  
Author(s):  
M Kimoto ◽  
T J Krenz ◽  
C G Fathman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presenting Cells ◽  
High Responder ◽  
Gene Products ◽  
T Cell Clones ◽  
Functional Capabilities ◽  
Cell Clones ◽  
Low Responder ◽  
Antigen Presenting

Long-term-cultured poly(Tyr, Glu)-poly-D,L,-Ala-poly-Lys [(T,G)-A--L]-reactive T cells and clones derived from (high responder x low responder)F1 [(C57BL/6 x A/J)F1] mice were shown to recognize (T,G)-A--L presented by cells from low responder strain A/J mice. The antigen-presenting determinant(s) that allowed recognition of (T,G)-A--L by such T cell clones was controlled by the I-A subregion of the major histocompatibility complex. These results suggest that there is no functional defect in the ability of low responder Ir gene products (I-A antigens) to associate with (T,G)-A--L for effective recognition by T cells. Although these results might tentatively be interpreted to suggest that Ir gene-controlled low responsiveness is due to the inability of the T cell to recognize the association between (T,G)-A--L and low responder I-A gene products, it is similarly possible that there might be a defect in the functional capabilities of low responder antigen-presenting cells to effectively process (T,G)-A--L into immunodominant epitopes.

scholarly journals The heme moiety of cytochrome c is an autoreactive Ir gene-restricted T cell epitope.

1988 ◽  
Vol 168 (3) ◽  
pp. 1127-1143 ◽  
Author(s):  
H M Cooper ◽  
G Corradin ◽  
Y Paterson
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Proliferative Response ◽  
Cell Epitope ◽  
Cell Populations ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Cell Clones ◽  
Cyt C

In these studies, we have shown that the heme moiety of cyt c is a dominant T cell epitope that induces a large proliferative response in lymph node T cells derived from SJL and B10.A mice when presented on either unfixed or fixed syngeneic APCs. Not only is this vigorous response observed for cyt c-primed T cell populations but also for populations obtained from naive SJL or B10.A mice. The reactivity to the heme moiety falls under strict MHC restriction, in that it is present only in murine strains bearing either the I-Ak or I-As molecule and can be blocked by antibodies specific for these class II molecules. Therefore, these findings require that the current models describing the nature of T cell epitopes be extended to include nonpeptide molecules. Furthermore, as the heme moiety is ubiquitous throughout the organism, although sequestered within proteins, the existence of heme-reactive T cell populations in unprimed animals provides another example of the existence of self-reactive T cell clones.

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