scholarly journals Selection of restriction specificities of virus-specific cytotoxic T cells in the thymus: no evidence for a crucial role of antigen-presenting cells.

1982 ◽  
Vol 156 (6) ◽  
pp. 1842-1847 ◽  
Author(s):  
R M Zinkernagel
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Antigen Presenting Cells ◽  
Cytotoxic T Cell ◽  
Antigen Presenting ◽  
Thymus Cells ◽  
Bone Marrow Chimeras

The proposal was tested that (P1 X P2) F1 leads to P1 irradiation bone marrow chimeras expressed predominantly P1-restricted T cells because donor derived stem cells were exposed to recipient derived antigen-presenting cells in the thymus. Because P1 recipient-derived antigen-presenting cells are replaced only slowly after 6-8 wk by (P1 X P2) donor-derived antigen-presenting cells in the thymus and because replenished pools of mature T cells may by then prevent substantial numbers of P2-restricted T cells to be generated, a large portion of thymus cells and mature T cells were eliminated using the following treatments of 12-20-wk-old (P1 X P2) F1 leads to P1 irradiation bone marrow chimeras: (a) cortisone plus antilymphocyte serum, (b) Cytoxan, (c) three doses of sublethal irradiation (300 rad) 2d apart, and (d) lethal irradiation (850 rad) and reconstitution with T cell-depleted (P1 X P2) F1 stem cells. 12-20 wk after this second treatment, (P1 X P2) leads to P1 chimeras were infected with vaccinia-virus. Virus-specific cytotoxic T cell reactivity was expressed by chimeric T cells of (P1 X P[2) F1 origin and was restricted predominantly to P1. Virus-specific cytotoxic T cells, therefore, do not seem to be selected to measurable extent by the immigrating donor-derived antigen-presenting cells in the thymus; their selection depends apparently from the recipient-derived radioresistant thymus cells.

scholarly journals CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages

2020 ◽  
Vol 4 (12) ◽  
pp. 2595-2605 ◽  
Author(s):  
Ole Audun W. Haabeth ◽  
Kjartan Hennig ◽  
Marte Fauskanger ◽  
Geir Åge Løset ◽  
Bjarne Bogen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Bone Marrow Microenvironment ◽  
Cd4 T Cell ◽  
Myeloma Cells ◽  
Antigen Presenting

Abstract CD4+ T cells may induce potent antitumor immune responses through interaction with antigen-presenting cells within the tumor microenvironment. Using a murine model of multiple myeloma, we demonstrated that adoptive transfer of idiotype-specific CD4+ T cells may elicit curative responses against established multifocal myeloma in bone marrow. This finding indicates that the myeloma bone marrow niche contains antigen-presenting cells that may be rendered tumoricidal. Given the complexity of the bone marrow microenvironment, the mechanistic basis of such immunotherapeutic responses is not known. Through a functional characterization of antitumor CD4+ T-cell responses within the bone marrow microenvironment, we found that killing of myeloma cells is orchestrated by a population of bone marrow–resident CD11b+F4/80+MHC-IIHigh macrophages that have taken up and present secreted myeloma protein. The present results demonstrate the potential of resident macrophages as powerful mediators of tumor killing within the bone marrow and provide a basis for novel therapeutic strategies against multiple myeloma and other malignancies that affect the bone marrow.

scholarly journals Killer artificial antigen-presenting cells: a novel strategy to delete specific T cells

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3546-3552 ◽  
Author(s):  
Christian Schütz ◽  
Martin Fleck ◽  
Andreas Mackensen ◽  
Alessia Zoso ◽  
Dagmar Halbritter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Fas Ligand ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses ◽  
Antigen Presenting

Abstract Several cell-based immunotherapy strategies have been developed to specifically modulate T cell–mediated immune responses. These methods frequently rely on the utilization of tolerogenic cell–based antigen-presenting cells (APCs). However, APCs are highly sensitive to cytotoxic T-cell responses, thus limiting their therapeutic capacity. Here, we describe a novel bead-based approach to modulate T-cell responses in an antigen-specific fashion. We have generated killer artificial APCs (κaAPCs) by coupling an apoptosis-inducing α-Fas (CD95) IgM mAb together with HLA-A2 Ig molecules onto beads. These κaAPCs deplete targeted antigen-specific T cells in a Fas/Fas ligand (FasL)–dependent fashion. T-cell depletion in cocultures is rapidly initiated (30 minutes), dependent on the amount of κaAPCs and independent of activation-induced cell death (AICD). κaAPCs represent a novel technology that can control T cell–mediated immune responses, and therefore has potential for use in treatment of autoimmune diseases and allograft rejection.

scholarly journals The lymphoreticular system in triggering virus plus self-specific cytotoxic T cells: evidence for T help.

1978 ◽  
Vol 147 (3) ◽  
pp. 897-911 ◽  
Author(s):  
R M Zinkernagel ◽  
G N Callahan ◽  
A Althage ◽  
S Cooper ◽  
J W Streilein ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Phenotypic Expression ◽  
Cell Activity ◽  
Thymic Epithelial Cells ◽  
Cytotoxic T Cell ◽  
Immunological Interactions

The thymus determines the spectrum of the receptor specificities of differentiating T cells for self-H-2; however, the phenotypic expression of T cell's specificity for self plus virus is determined predominantly by the H-2 type of the antigen presenting cells of the peripheral lymphoreticular system. Furthermore, virus specific helper T cells are essential for the generation of virus-specific cytotoxic T cells. For cooperation between mature T cells and other lymphocytes to be functional in chimeras, thymic epithelial cells and lymphohemopoietic stem cells must share the I region; killer T-cell generation also requires in addition compatibility for at least one K or D region. These conclusions derive from the following experiments: A leads to (A X B)F1 chimeric lymphocytes do produce virus-specific cytotoxic T-cell activity for infected A but not for infected B cells; when sensitized in an acutely irradiated and infected recipient (A X B)F1 these chimeric lymphocytes respond to both infected A and B. Therefore the predominantly immunogenically infected cells of chimeras the radiosensitive and by donor stem cells replaced lymphoreticular cells. In this adoptive priming model (KAIA/DB leads to KAIA/DC) chimeric lymphocytes could be sensitized in irradiated and infected F1 against KA and DC but not against infected DB targets. In contrast KBIB/DA leads to KCIC/DA chimeras' lymphocytes could not be sensitized at all in appropriately irradiated and infected F1 recipients. Thus these latter chimeras probably lack functional I-specific T helper cells that are essential for the generation of T killer cells against infected D compatible targets. If T cells learn in the thymus to recognize H-21 or K, D markers that are not at least partially carried themselves in other cells of the lymphoreticular system immunological interactions will be impossible and this paradox situation results in phenotypic immune incompetence in vivo.

scholarly journals Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3390-3397 ◽  
Author(s):  
Laurent Burnier ◽  
François Saller ◽  
Linda Kadi ◽  
Anne C. Brisset ◽  
Rocco Sugamele ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Antigen Presenting Cells ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Antigen Presenting

Abstract Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6−/− mice received allogeneic non–T cell–depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6−/− recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6−/− recipients' liver. When mice received 0.5 × 106 allogeneic T cells with T cell–depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6−/− than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6−/− T-cell proliferation. We therefore assessed the response of WT or Gas6−/− ECs to tumor necrosis factor-α. Lymphocyte transmigration was less extensive through Gas6−/− than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.

Increased Cytotoxic T-Cell Infiltrates in the Bone Marrow Is an Independent Adverse Prognostic Factor in Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1492-1492
Author(s):  
Grzegorz S. Nowakowski ◽  
Chin-Yang Li ◽  
David Dingli ◽  
Shaji Kumar ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Immune Response ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Prognostic Factor ◽  
Cytotoxic T Cells ◽  
Cytotoxic T Cell ◽  
Newly Diagnosed

Abstract Background: Cytotoxic T-cell infiltrates are a nearly universal finding in the bone marrow of patients with multiple myeloma. It has been postulated that presence of T-cells in the bone marrow of multiple myeloma (MM) patients represents an immune response against the tumor and therefore, might be associated with an improved prognosis. However, the impact of bone marrow T-cells on the prognosis of multiple myeloma patients has not been studied systematically. Methods: Bone marrow biopsies of patients with newly diagnosed multiple myeloma were stained by immnohistochemistry for the CD8 antigen and reviewed by a blinded hematopathologist. Three high power fields are reviewed for each biopsy and the total number of CD8 positive cells counted and reported. For patients with more than 300 cells per 3 fields, results were reported as >300. The number of bone marrow CD8 positive cells was then correlated with patients’ clinical data, including other prognostic factors and overall survival. Results: Bone marrow biopsy specimens from 100 patients, performed within the week of a diagnosis of multiple myeloma and collected between May 1998 and January 2001 were evaluated. The median number of CD8 positive cells was 270 (33 – >300). Patients’ characteristics are shown in Table 1. Median follow up was 30 months (0–80). The number of cytotoxic T-cells as a continuous variable was a risk factor for shortened overall survival, HR 1.86 (95% CI 1.11–3.35). Using minimal p value approach, the cutoff of 270 cells (the median) risk stratified patients into two groups: the median survival of patients with > 270 CD8 positive cells was 16 months vs. 48 months in patients with ≤270 cells, p=0.005 (Figure). In multivariate analysis including age, B2M, albumin, CRP, bone marrow plasma cell percentage and plasma cell labeling index, the number of cytotoxic T-cells was an independent predictor of overall survival was HR 3.1, p=0.0017. Conclusion: We show that the number of cytotoxic T-cells in the bone marrow is a strong and independent prognostic factor in patients with newly diagnosed multiple myeloma. Our observation does not contradict the hypothesis that cytotoxic T-cells participate in an immune response against the tumor since our findings may represent a higher level of immune response associated with baseline aggressive disease biology. However, our study suggests for the first time that increased marrow cytotoxic T-cells have an adverse effect on outcome in myeloma, and suggest that these cells may have a direct facilitating effect on tumor growth and on the marrow microenvironment. Further studies of the biology of behind this observation are warranted. Characteristic N Median (range) Gender male 61 CRP 81 0.4mg/L (0.01–11.2) Albumin 99 3.6 g/dL (2.6–5.4) B2microglobulin 94 4.0 (0.9–28) μg/mL Marrow PC% 90 45% (11–99) PC labeling index 90 high (>1%) 36 BM CD8 cells 100 270 (33 – >300) ISS 94 1 19 2 41 3 34 Figure Figure

Neutrophils efficiently cross-prime naive T cells in vivo

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2965-2973 ◽  
Author(s):  
Céline Beauvillain ◽  
Yves Delneste ◽  
Mari Scotet ◽  
Audrey Peres ◽  
Hugues Gascan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cross Presentation ◽  
Antigen Presenting

Abstract Neutrophils are professional phagocytes that migrate early, in high number, to the infection sites. Our study has analyzed how neutrophils cross-present antigens and influence CD8+ T-cell responses. By using highly purified neutrophils from peritoneal exudates and bone marrow, we have shown that neutrophils cross-present ovalbumin to a CD8+ T-cell hybridoma and to naive CD8+ T cells from OT1 transgenic mice. Cross-presentation by neutrophils was TAP and proteasome dependent and was as efficient as in macrophages. Moreover, it actually occurred earlier than in professional antigen-presenting cells. Peritoneal exudate neutrophils from mice injected intraperitoneally with ovalbumin also cross-presented ovalbumin, proving that neutrophils take up and present exogenous antigens into major histocompatibility complex I (MHC I) molecules in vivo. We then evaluated the in vivo influence of antigen cross-presentation by neutrophils on CD8+ T-cell response using β2-microglobulin-deficient mice transferred with OT1 CD8+ T cells and injected with ovalbumin-pulsed neutrophils. Four days after neutrophil injection, OT1 cells proliferated and expressed effector functions (IFN-γ production and cytolysis). They also responded efficiently to a rechallenge with ovalbumin-pulsed dendritic cells in CFA. These data are the first demonstration that neutrophils cross-prime CD8+ T cells in vivo and suggest that they may constitute, together with professional antigen-presenting cells, an attractive target to induce cytotoxic T cells in vaccines.

scholarly journals Requirements for Bone Marrow–Derived Antigen-Presenting Cells in Priming Cytotoxic T Cell Responses to Intracellular Pathogens

2000 ◽  
Vol 192 (8) ◽  
pp. 1135-1142 ◽  
Author(s):  
Laurel L. Lenz ◽  
Eric A. Butz ◽  
Michael J. Bevan
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Antigen Presentation ◽  
Antigen Presenting Cells ◽  
Cytotoxic T Cell ◽  
Chimeric Mice ◽  
Cytotoxic T Cell Responses ◽  
Antigen Presenting ◽  
Ctl Responses

Bone marrow (BM)-derived antigen-presenting cells (APCs) are potent stimulators of T cell immune responses. We investigated the requirements for antigen presentation by these cells in priming cytotoxic T lymphocyte (CTL) responses to intracellular bacterial and viral pathogens. [Parent→F1] radiation BM chimeras were constructed using C57BL/6 donors and (C57BL/6 × BALB/c)F1 recipients. Infection of chimeric mice with either Listeria monocytogenes or vaccinia virus expressing the nucleoprotein (NP) antigen from lymphocytic choriomeningitis virus (LCMV) primed H2-Db–restricted, but not H2-Kd–restricted CTL responses, demonstrating the requirement for BM-derived APCs for successful priming of CTL responses to these pathogens. Surprisingly, this did not hold true for chimeric mice infected with LCMV itself. LCMV-infected animals developed strong CTL responses specific for both H2-Db– and H2-Ld–restricted NP epitopes. These findings indicate that in vivo priming of CTL responses to LCMV is remarkably insensitive to deficiencies in antigen presentation by professional BM-derived APCs.

scholarly journals CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3475-3484 ◽  
Author(s):  
Josef Kurtz ◽  
Forum Raval ◽  
Casey Vallot ◽  
Jayden Der ◽  
Megan Sykes
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Bone Marrow Cells ◽  
Antigen Presenting Cells ◽  
Cd4 T Cell ◽  
Cell Tolerance ◽  
Antigen Presenting ◽  
Marrow Cells

Abstract Although the inhibitory receptor CTLA-4 (CD152) has been implicated in peripheral CD4 T-cell tolerance, its mechanism of action remains poorly defined. We analyzed mechanisms of CD4 cell tolerance in a model of tolerance induction involving establishment of mixed hematopoietic chimerism in recipients of fully MHC-mismatched allogeneic bone marrow cells with anti-CD154 mAb. Animals lacking CD80 and CD86 failed to achieve chimerism. We detected no T cell–intrinsic requirement for CD28 for chimerism induction. However, a CD4 T cell–intrinsic signal through CTLA-4 was shown to be essential within the first 48 hours of exposure to alloantigen for the establishment of tolerance and mixed chimerism. This signal must be provided by a recipient CD80/86+ non–T-cell population. Donor CD80/86 expression was insufficient to achieve tolerance. Together, our findings demonstrate a surprising role for interactions of CTLA-4 expressed by alloreactive peripheral CD4 T cells with CD80/86 on recipient antigen-presenting cells (APCs) in the induction of early tolerance, suggesting a 3-cell tolerance model involving directly alloreactive CD4 cells, donor antigen-expressing bone marrow cells, and recipient antigen-presenting cells. This tolerance is independent of regulatory T cells and culminates in the deletion of directly alloreactive CD4 T cells.

scholarly journals Ex Vivo Generation of Human Anti–Pre-B Leukemia-Specific Autologous Cytolytic T Cells

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 549-561 ◽  
Author(s):  
Angelo A. Cardoso ◽  
Mark J. Seamon ◽  
Hernani M. Afonso ◽  
Paolo Ghia ◽  
Vassiliki A. Boussiotis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Antigen Presenting Cells ◽  
Cell Leukemia ◽  
B Cell Leukemia ◽  
Antigen Presenting

Abstract In contrast to other neoplasms, antigen-specific autologous cytolytic T cells have not been detected in patients with human pre-B–cell leukemias. The absence of efficient B7 family (B7-1/CD80; B7-2/CD86) -mediated costimulation has been shown to be a major defect in tumor cells' capacity to function as antigen-presenting cells. We show here the generation of autologous anti–pre-B–cell leukemia-specific cytolytic T-cell lines from the marrows of 10 of 15 patients with pre-B–cell malignancies. T-cell costimulation via CD28 is an absolute requirement for the generation of these autologous cytolytic T cells (CTL). Although costimulation could be delivered by either bystander B7 transfectants or professional antigen-presenting cells (indirect costimulation), optimal priming and CTL expansion required that the costimulatory signal was expressed by the tumor cell (direct costimulation). These anti–pre-B–cell leukemia-specific CTL lysed both unstimulated and CD40-stimulated tumor cells from each patient studied but did not lyse either K562 or CD40-stimulated allogeneic B cells. Cytolysis was mediated by the induction of tumor cell apoptosis by CD8+ T cells via the perforin-granzyme pathway. Although we were able to generate anti–leukemia-specific CTL from the bone marrow, we were unable to generate such CTL from the peripheral blood of these patients. These studies show that antigen-specific CTL can be generated from the bone marrow of patients with pre-B–cell leukemias and these findings should facilitate the design of adoptive T-cell–mediated immunotherapy trials for the treatment of patients with B-cell precursor malignancies.

A Panel of Artificial Antigen-Presenting Cells (AAPC) Expressing Prevalent HLA Alleles Permits Generation of Cytotoxic T Cells Specific for Both Subdominant and Dominant Viral Epitopes for Adoptive Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2589-2589 ◽  
Author(s):  
Aisha Hasan ◽  
Wouter J. Kollen ◽  
A. Selvakumar ◽  
D. Trivedi ◽  
M. Sadelain ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peptide Pool ◽  
Antigen Presenting Cells ◽  
Cytotoxic T Cell ◽  
Cell Transplant ◽  
Adoptive Therapy ◽  
Hematopoietic Stem ◽  
Hla Alleles ◽  
Antigen Presenting

Abstract Adoptive transfer of antigen specific T cells can be effective in treating viral infections complicating allogeneic hematopoietic stem cell transplant (HSCT) recipients. However, in practice, generation of T cells is often limited by insufficient supply of autologous antigen presenting cells; therapeutic activity in HLA disparate patients may also be impaired if the immuno- dominant T cells generated are restricted by HLA alleles not shared by the host. AAPCs have theoretical advantages for T cell therapies in terms of sustained supply and capacity to selectively stimulate T cells restricted by HLA alleles shared by donor and host. However, to date, only AAPC systems expressing HLA A*0201 have been characterized. Accordingly, we established a panel of AAPC consisting of NIH 3T3 mouse fibroblast cells, each transduced to express β2- microglobulin and a prevalent HLA class-I allele, specifically HLA A*0201, A*0301, A*2402, B*0702, B*0801 or C*0401, as well as the human co-stimulatory molecules B7.1, LFA-3 and ICAM-1. Novel promotor sequences were introduced to secure stable high expression of the allele on the AAPCs. Sensitization of T cells from seropositive donors with AAPCs expressing each of these alleles (4-8 donors/allele), either loaded with overlapping 15-mer peptides spanning the CMVpp65 sequence or transduced to express the CMV pp65 protein, resulted in 12-35 fold expansions of CD8 + T cells exhibiting CMV pp65 epitope-specific, HLA restricted activity, as quantitated by peptide -HLA tetramer binding, epitope specific production of interferon gamma, and cytotoxic activity against peptide loaded or CMV infected targets. Although both peptide pool loaded and transduced AAPCs induce CMV pp65 epitope specific T cells, yields were higher when transduced AAPCs were employed. In studies of T-cells from 5 donors when sensitized with either peptide pool loaded autologous dendritic cells (DC) or HLA sharing AAPCs, sensitization with DC selectively induced T-cells specific for 1-2 immunodominant CMV pp65 epitopes. In contrast, while sensitization with a panel of peptide loaded or transduced AAPCs expressing shared HLA alleles elicited responses to the same dominant epitopes, we could also regularly generate comparable cytotoxic T cell responses to subdominant epitopes which were either not produced or only present at low frequencies in T cells sensitized with autologous DC. Thus, this panel of AAPCs stably expressing a series of HLA alleles which, in aggregate, are detected in 70% of the patients referred for HSCT, can be employed for rapid generation of CMV-pp65 specific T cells of desired HLA restriction for adoptive therapy.

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