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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the acquisition of self tolerance in the thymus, full-allogeneic thymic chimeras were constructed. Athymic C3H and BALB/c nude mice were reconstituted with the thymic lobes of BALB/c and B10.BR fetuses, respectively, that were organ cultured for 5 days in the presence of 2'-deoxyguanosine. T cells in these chimeras were tolerized to the host MHC in both MLR and CTL assays. In contrast, T cells in the chimeras exhibited split tolerance for the thymic MHC haplotype. CTL specific for class I MHC of the thymic haplotype were generated not only from the peripheral T cells of the chimeras but also from thymocytes re-populated in the engrafted thymic lobes. However, T cells in these chimeras responded poorly to the class II MHC of the thymic haplotype in a standard MLR assay. In a syngeneic MLR culture upon stimulation with enriched APC of the thymic haplotype, only 22 to 48% of the responses were mediated by CD4+ cells, and proliferations of CD4- cells were prominent. There were no haplotype-specific suppressor cells detected which would cause the unresponsiveness to the thymic class II MHC. These results indicated that the thymic lobes treated with 2'-deoxyguanosine were defective in the ability to induce the transplantation tolerance for the class I MHC expressed on the thymus, although the same thymic lobes were able to induce the transplantation tolerance for the thymic class II MHC.
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PMID:Split tolerance in nude mice transplanted with 2'-deoxyguanosine-treated allogeneic thymus lobes. 252 79

The interaction of TCR, antigen, and MHC complex has been analyzed using synthetic peptide antigens and a series of single amino acid-substituted analogues. Two similar antigens, mouse cytochrome c (mcyt c) and pigeon cytochrome c (pcyt c), elicit T cell responses in strains of mice bearing MHC class II Ek beta Ek alpha (B10.A), Eb beta Ek alpha [B10.A(5R)], and Es beta Ek alpha [B10.S(9R)]. The immunogenic regions of these antigens are located in the peptide sequence p88-104 for pcyt c and m88-103 for mcyt c. The limited T cell repertoire for these antigens is comprised of four groups of T cell phenotypes that have very few differences in their TCR gene make up. In this paper, we examine the diversity in their fine specificity for each of the antigens, m88-103 and p88-104, complexed with each of the I-Ek haplotypes. Epitopes, i.e., residues that interact with the TCR, and agretopes, i.e., residues in the MHC-binding site, were assigned for the two peptide antigens in the presence of APC bearing E beta kEk alpha, Eb beta Ek alpha, or Eb beta Ek alpha using T cell hybridomas of the phenotypes I, IIIa, and IV. From our results, we conclude that first, the substitution of any residue between 95 and 104 of the cytochrome c peptide changed the antigenic potency of the peptide for at least one of the hybridomas. Second, each T cell type has a different recognition pattern of epitopes and agretopes for a particular antigen-MHC complex, thus, ruling out a static model of T cell recognition, which assigns certain, invariant agretopic residues to the peptide by which it interacts with the MHC molecule independently of the TCR. Third, the same T cell hybridoma responded to the antigens differently when presented on various MHC molecules, implying that overall changes in the MHC groove, as displayed by the three haplotypes, may affect the efficiency in binding the peptide. Fourth, since most of the residues are used as epitopes by at least one of the T cell specificities, the peptide appears to be recognized in a different conformation by each T cell hybridoma phenotype; and, finally, the epitopic and agretopic residues do not segregate, for any one of the T cell specificities, in such a way that suggests they are recognized in a helical conformation. In summary, our results suggest that a single peptide may generate diversity in the T cell response by virtue of its conformational flexibility within the TCR-MHC-antigen complex.
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PMID:Analysis of peptide binding patterns in different major histocompatibility complex/T cell receptor complexes using pigeon cytochrome c-specific T cell hybridomas. Evidence that a single peptide binds major histocompatibility complex in different conformations. 255 48

This paper describes an adjuvant-free immunization regimen that results in the priming of T cells but not B cells. B10.A mice were primed s.c. with syngeneic spleen cells that had been pulsed with the peptide 81-104 derived from pigeon cytochrome c. The T cell response was measured by using a sensitive limiting dilution assay that measures lymphokine production. The precursor frequency of Ag-specific cells found in these mice was indistinguishable from the frequency found in mice primed in the footpads with 81-104 in CFA. A striking difference in antibody induction was found, however, when these two immunization regimens were compared. Mice primed with 81-104 in CFA developed significant serum antibody responses against the peptide, whereas mice primed with Ag-pulsed spleen cells produced no detectable anti-peptide antibodies. This lack of antibody did not result from detectable differences in the T cells that were primed: no differences were seen in IL-2 and IL-4 production or in the ability to provide help to B cells in vitro. In vitro stimulation with LPS suggested that the B cells were not primed by the Ag-pulsed spleen cells. The B cells were not tolerized, however, because boosting the mice with Ag in CFA resulted in the induction of an antibody response. The failure to induce an antibody response by priming with Ag-pulsed spleen cells was not caused by the site of immunization or the total amount of Ag used for priming. The critical variable may be the introduction of the Ag on the surface of an APC; in this form, B cell Ag recognition was apparently inefficient, whereas T cell Ag recognition was optimal.
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PMID:In vivo priming of helper T cells in the absence of B cell activation. 255 72

Immune responsiveness to lysozyme in H-2b mice is under the control of H-2-linked Ir genes, with T suppressor (Ts) cells playing a dominant role in strains such as C57BL/6 (B6), C57BL/10 and A.BY. However, non-H-2-genes were found to be capable of specific reversal of the effect of the H-2-linked genes in responsiveness to chicken lysozyme (HEL), but not to human lysozyme (HUL). Therefore, studies were performed to identify any lesion in the suppressor circuit in BALB.B. It was known that HUL-induced suppressor cells could cross-suppress the anti-HEL response in B10.Q mice, which are responsive to HEL but nonresponsive to HUL. Similarly, BALB.B Ts cells were able to suppress the anti-HEL response, using as T helper (Th) source a T cell line (BB-1), derived from HEL-primed BALB.B periaortic and inguinal lymph node cells. A protocol designed to examine the in vivo suppression by the use of HUL-induced suppressor cells also demonstrated a significant suppression of the anti-HEL response. Since the suppressive circuitry seemed intact in the BALB.B, the possibility was examined that a step in T-B cell collaboration was more efficient in this strain than in the B6 nonresponder. With a B6-derived HEL-specific T cell line, BO1H, the B cell and antigen-presenting (B/APC) populations from B6 required addition of concanavalin A supernatant for anti-HEL antibody formation, whereas BALB.B B/APC were capable of responding to HEL in culture without the addition of concanavalin A supernatant. In agreement with this finding, when B/APC cell populations from BALB.B and B6 were compared for their extent of anti-HEL responsiveness, as measured with BB-1 Th cells, BALB.B B/APC populations responded significantly higher than B6 populations when the responses were activated by picogram/nanogram amounts of HEL. The response level of (BALB.B X B6)F1 B/APC measured in the same assay resembled that of B6. However, when HEL was used at the microgram level, both B6 and BALB.B strains responded equivalently. The above data are consistent with the expression of the reversing non-H-2 Ir gene(s) resulting from the balance of antigen presentation to Th and Ts cells in the H-2b mouse. In the B6, processing and handling of antigen may be inefficient in activating response-enhancing Th, and more effective in triggering Ts cells, while the reverse may be true for the BALB.B.
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PMID:Selective reversal of H-2-linked genetic unresponsiveness to lysozymes. II. Alteration in the T helper/T suppressor balance, owing to gene(s) linked to Ir-2, leads to responsiveness in BALB.B. 293 74

The protein Ag, tobacco mosaic virus protein, (TMVP) and its tryptic peptide number 8 (residues 93-112 of the protein) exhibit cross-reactivity on the T cell level in some strains of mice (e.g., C3H.SW, C57BL/10); these strains are termed cross-reactive (CR). In other strains such as A/J or B10.BR, no cross-reactivity is exhibited; these strains are termed non-cross-reactive (NCR). Genetic experiments indicated that the cross-reactivity is dominant and that it is mapped to the I-A or I-E region of the MHC, with cross-reactivity exhibited by the I-Ab haplotype but not by I-Ak or I-Ek. Cell reconstitution experiments have indicated that the non-cross-reactivity is associated with the inability of the NCR APC to present Ag. Analysis of the area(s) on peptide 8 which serve(s) as epitope revealed that both strains recognize an overlapping area consisting of 11 amino acid residues in the middle of peptide 8 (residues 97-107), which by itself is nonstimulatory to TMVP- or peptide 8-immune T cells of the CR or the NCR strains. However, the addition of a few amino acid residues of the sequence of peptide 8 to this area converts it to a complete stimulatory epitope. Additivity experiments revealed that the CR strain contains two major T cell populations each recognizing this middle region of peptide 8 when elongated by a few amino acids N-terminally and C-terminally, respectively. In contrast, the NCR strain contains one major T cell population recognizing elongation only N-terminally. Because TMVP (but not peptide 8) requires processing before presentation to T cells, it is postulated that, during processing of TMVP, there occur alterations in the area of the proximal three or four N-terminal amino acids of the region consisting of peptide 8, destroying the only region containing the T cell epitope recognized by the NCR strain, hence TMVP and peptide 8 do not exhibit cross-reactivity in this strain. The same alterations of TMVP still leave intact an epitope consisting of amino acid residues C-terminal to the altered area which is recognized by the CR strain, hence the cross-reactivity exhibited by this strain. The results suggest that the difference in cross-reactivity on the T cell level between TMVP and peptide 8 exhibited by the strains may be due to differences in the orientation of presentation and the subsequent cell recognition of an epitope contained within peptide 8.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Structural features of an antigen required for cellular interactions and for T cell activation in a MHC-restricted response. 326 Feb 52

Although studies of the association of antigen with APC have been complicated by antigen-processing requirements, recent studies have suggested that immunologically relevant antigen should be present on the APC surface. Nevertheless, blocking of antigen presentation with antibody to the antigen has not been demonstrable in most systems. To study this problem we developed a system using avidin to block presentation of amino-terminal biotinylated synthetic peptide 132-146 of sperm whale myoglobin (B132) to a murine T cell clone specific for this site in association with I-Ed. greater than 95% specific inhibition was observed with doses of B132 equipotent to unmodified peptide. Specific blocking could be observed: (a) after pulsing APC with antigen, washing, and incubating for a chase period of 8-16 h before addition of avidin and T cells to assure adequate time for intracellular trafficking and maximal display of antigen on the cell surface, or (b) when monensin is present during the antigen pulse to inhibit such traffic. Therefore, the inhibition appeared to be occurring at the cell surface unless dissociation and reassociation were constantly occurring. To distinguish these, B10.GD APC (I-Ed-negative) were pulsed with antigen and cocultured with B10.D2 APC (I-Ed-positive). No detectable antigen presentation resulted. Thus, minimal dissociation and reassociation between antigen and APC occurs and, consequently, blocking by extracellular solution-phase binding of avidin to antigen is unlikely. Taken together, these data suggest that the blocking is occurring at the cell surface. Thus, under physiologic conditions, immunologically relevant antigen necessary for T cell activation appears to be present on the APC surface and is freely accessible to macromolecules the size of avidin. These findings hold specific implications for models of antigen presentation for T cell recognition.
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PMID:Immunologically relevant peptide antigen exists on the presenting cell in a manner accessible to macromolecules in solution. 349 May 31

10BK.1 T clone cells of (B10 x B10.BR)F1 genotype specifically react to peptides of OVA, frequently encountered in OVA preparations, and to the synthetic peptide OVA257-264 in an H-2Kb-restricted manner; the T clone cells produce lymphokines and proliferate in the absence of added APC, suggesting self-presentation of the Ag by the T cells. In accordance with their CD8+ CD4- phenotype 10BK.1 cells exhibit cytotoxic capacity. When the target cells were pretreated with OVA257-264 only cells bearing H-2Kb molecules were lysed. However, when the relevant OVA peptide was present during the 4-h 51Cr release assay 10BK.1 cells lysed target cells expressing H-2Kb molecules as well as target cells lacking H-2Kb elements. Likewise, 10BK.1 cells pretreated with OVA257-264 for 1 h and washed extensively to remove residual Ag were able to kill syngeneic and allogeneic target cells. Killing of allogeneic targets in the presence of Ag was inhibited by antibodies directed at H-2Kb. Allogeneic target cells were not killed when 10BK.1 cells were stimulated by peptide-pulsed syngeneic cells. Triggering of the TCR/CD3 complex of 10BK.1 cells was involved during the activation phase but not during the lytic phase. IL-2 did not participate in the MHC-unrestricted killing event. To explain the observed MHC-unrestricted cytotoxicity of 10BK.1 cells, the following model is proposed. In an initial step 10BK.1 cells present the relevant OVA peptide to one another in a H-2Kb-restricted fashion. The cells are thereby triggered to mobilize the lytic machinery. In a second step sensitized 10BK.1 cells lyse allogeneic target cells. Thus, the MHC-unrestricted cytotoxicity can be dissected into an MHC-restricted phase of 10BK.1 cell activation and an MHC-unrestricted lytic phase. Cytotoxic T cells with Ag self-presentation functions may account for tissue damage during bacterial infections.
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PMID:Manifestation of the MHC-unrestricted killing potential of a cytotoxic T cell clone requires activation in response to MHC-restricted self-presentation of antigen. 845 44

Allogeneic tissues transplanted to mice treated with CD4- and CD8-specific Abs are often accepted indefinitely due to the induction of immunologic tolerance. When transplantation tolerance was induced to grafts mismatched at multiple minor histocompatibility loci, Ag specificity was inferred because third party grafts, mismatched at the MHC, were rejected normally. However, some "third party" grafts were either accepted, or rejected more slowly. Tolerant mice possess CD4+ cells, which suppress rejection by T cells reacting to the same grafts. Therefore, we hypothesized that tolerated third party grafts might share Ags with the original tolerizing graft, and that these Ags are a target for such suppression. To test this idea, we tolerized mice to a set of minor Ags (B10 minors) and challenged them with third party grafts that carried those minors, as well as an additional strong transplantation Ag, the class I MHC molecule, H-2Kb. This class I molecule acts as a good target for rejection in both naive mice and in mice tolerized to B10 minors. However, when this third party class I molecule is provided "linked" to those B10 minors on an F1 graft, rejection was significantly impaired. The data suggest that suppression within tolerant animals operates locally (perhaps on the same APC) via linked recognition. In addition, our preliminary findings suggest that suppression via linked recognition can also lead to tolerance to the third party Ag.
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PMID:T cell suppression in transplantation tolerance through linked recognition. 862 93

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.
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PMID: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. 862 65

Mouse livers are accepted across MHC barriers and induce donor-specific tolerance without immunosuppressive therapy. By contrast, livers from donors treated with Flt3 ligand, which dramatically increases hepatic interstitial dendritic cells, are rejected acutely (median survival time 5 days). This switch from tolerance to rejection is associated with a marked reduction in apoptotic activity of graft-infiltrating cells. We hypothesized that IL-12 production by enhanced numbers of donor APC might inhibit apoptosis, promote expansion of Th1 cells, and play a key role in liver rejection. Therefore, C3H (H2(k)) recipients of liver grafts from Flt3 ligand-treated B10 donors were given neutralizing anti-IL-12 mAb (200 or 500 microg) on days 0 and 2 after transplant. Graft survival was markedly prolonged at the higher mAb dose, with 50% of grafts surviving >100 days. This effect was associated with reductions in IFN-gamma gene transcripts within the graft-infiltrating cell population and with reductions in circulating IFN-gamma and IL-10 levels, donor-specific CTL and NK cell activities, and circulating alloantibody levels. At the same time, there were marked increases in apoptotic (TUNEL(+)) CD4(+) and especially CD8(+) cells, both within the grafts and in spleens of anti-IL-12 mAb-treated mice. In vitro, exogenous IL-12 inhibited apoptotic death induced in naive allogeneic T cells by liver nonparenchymal cells. These findings suggest that suppression of rejection by IL-12 antagonism, linked to restoration of apoptotic activity within the peripheral alloreactive T cell population, is important for liver allograft survival and tolerance induction.
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PMID:Il-12 antagonism enhances apoptotic death of T cells within hepatic allografts from Flt3 ligand-treated donors and promotes graft acceptance. 1131 2


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