scholarly journals Donor CD8 cells prevent allogeneic marrow graft rejection in mice: potential implications for marrow transplantation in humans.

1993 ◽  
Vol 178 (2) ◽  
pp. 703-712 ◽  
Author(s):  
P J Martin
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Cytotoxic T Cells ◽  
Class I ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Donor Cells ◽  
Donor T Cells ◽  
Allogeneic Marrow

Numerous experimental models have demonstrated that graft-vs.-host disease (GVHD) does not occur in irradiation chimeras when the graft does not contain mature, immunocompetent T lymphocytes, but clinical studies have shown that T cell depletion of donor marrow can be associated with a greatly increased risk of graft failure. We have developed a model where engraftment of (C57BL/6J x C3H/HeJ)F1 (B6C3) marrow in 800-cGy-irradiated (BALB/cJ x C57BL/6J)F1 (CB6) recipients depends on the presence of donor T cells in the graft. Recipients transplanted with 5.0 x 10(6) marrow cells depleted of T lymphocytes showed host lymphoid and myeloid reconstitution, whereas recipients transplanted with the same marrow plus 2.5 x 10(5) purified donor T cells showed donor reconstitution. Adding as few as 0.5 x 10(5) CD8-enriched donor T cells to marrow grafts containing 5.0 x 10(6) T cell-depleted donor cells was sufficient to enable donor reconstitution, while surviving recipients transplanted with the same marrow and 0.5-2.5 x 10(5) CD4-enriched donor cells showed only host reconstitution. To address the question of whether donor CD4 cells could facilitate engraftment under conditions where GVHD would not represent a limiting factor, engraftment of bm1 marrow was tested in major histocompatibility complex (MHC) class I-disparate B6.Ly5a recipients. Results indicated that the donor CD8-enriched population was at least fivefold more active than the CD4-enriched population for facilitating allogeneic marrow engraftment in this strain combination. Thus, the lymphokines and MHC class II-specific cytotoxic T cells generated by CD4 cells were relatively ineffective for enhancing engraftment, possibly reflecting the fact that the host T cells that contain effectors responsible for causing rejection do not express MHC class II antigens. The ability of donor CD8 cells to facilitate engraftment could reflect the activity of a cytokine uniquely elaborated after recognition of an MHC class I disparity. More likely, the graft-enhancing effect of donor CD8 cells may result from the generation of MHC class I-specific or class I-restricted cytotoxic T cells that recognize the host CD4 and CD8 cells responsible for causing rejection. The possibility remains that other mechanisms such as veto inactivation of host T cells by donor CD8 cells may also contribute to the graft-enhancing effect.

Prevention of allogeneic marrow graft rejection by donor T cells that do not recognize recipient alloantigens: potential role of a veto mechanism

Blood ◽  
1996 ◽  
Vol 88 (3) ◽  
pp. 962-969 ◽  
Author(s):  
PJ Martin
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Graft Rejection ◽  
Class Ii ◽  
Class I ◽  
Marrow Graft ◽  
Cd8 Cells ◽  
Donor T Cells ◽  
Veto Mechanism ◽  
Allogeneic Marrow

Clinical trials and experimental studies have demonstrated that donor T cells can play a critical role in preventing allogeneic marrow graft rejection. Results of a previous study showed that donor T cells were most effective for preventing rejection when they recognize an alloantigen expressed by recipient T cells and can cause graft-versus- host disease (GVHD). The present study examined models where marrow graft rejection can be prevented by donor T cells that do not recognize host alloantigens and cannot cause GVHD. Donor T cells prevented rejection of major histocompatibility complex (MHC) class I and II- disparate F1 marrow in parental recipients prepared with > or = 800 cGy total body irradiation (TBI) but not in those prepared with < or = 750 cGy TBI. In recipients prepared with high TBI exposures, rejection was mediated entirely by host CD8 cells. With lower TBI exposures, rejection was mediated by host CD4 cells and CD8 cells. These observations suggested the hypothesis that donor T cells prevent rejection mediated by host effectors that recognize donor MHC class I alloantigens but do not prevent rejection mediated by host effectors that recognize donor class II alloantigens. Consistent with this hypothesis, further experiments showed that F1 donor T cells can prevent rejection of MHC class I-disparate marrow in irradiated parental recipients but have no detectable effect on rejection of MHC class II-disparate marrow. We propose that the expression of MHC class I molecules on donor T cells makes it possible for these cells to inactivate the host response against donor class I alloantigens through a veto mechanism, whereas the absence of MHC class II molecules on murine T cells explains why these cells cannot inactivate the host response against donor class II alloantigens. Finally, donor CD4 cells and CD8 cells were equivalently effective for preventing rejection of F1 marrow in parental recipients, suggesting that veto activity is not restricted solely to the CD8 subset of murine T cells. A veto mechanism could enable donor T cells to prevent allogeneic marrow graft rejection without causing GVHD.

scholarly journals Prevention of allogeneic marrow graft rejection by donor T cells that do not recognize recipient alloantigens: potential role of a veto mechanism

Blood ◽  
1996 ◽  
Vol 88 (3) ◽  
pp. 962-969 ◽  
Author(s):  
PJ Martin
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Graft Rejection ◽  
Class Ii ◽  
Class I ◽  
Marrow Graft ◽  
Cd8 Cells ◽  
Donor T Cells ◽  
Veto Mechanism ◽  
Allogeneic Marrow

Abstract Clinical trials and experimental studies have demonstrated that donor T cells can play a critical role in preventing allogeneic marrow graft rejection. Results of a previous study showed that donor T cells were most effective for preventing rejection when they recognize an alloantigen expressed by recipient T cells and can cause graft-versus- host disease (GVHD). The present study examined models where marrow graft rejection can be prevented by donor T cells that do not recognize host alloantigens and cannot cause GVHD. Donor T cells prevented rejection of major histocompatibility complex (MHC) class I and II- disparate F1 marrow in parental recipients prepared with > or = 800 cGy total body irradiation (TBI) but not in those prepared with < or = 750 cGy TBI. In recipients prepared with high TBI exposures, rejection was mediated entirely by host CD8 cells. With lower TBI exposures, rejection was mediated by host CD4 cells and CD8 cells. These observations suggested the hypothesis that donor T cells prevent rejection mediated by host effectors that recognize donor MHC class I alloantigens but do not prevent rejection mediated by host effectors that recognize donor class II alloantigens. Consistent with this hypothesis, further experiments showed that F1 donor T cells can prevent rejection of MHC class I-disparate marrow in irradiated parental recipients but have no detectable effect on rejection of MHC class II-disparate marrow. We propose that the expression of MHC class I molecules on donor T cells makes it possible for these cells to inactivate the host response against donor class I alloantigens through a veto mechanism, whereas the absence of MHC class II molecules on murine T cells explains why these cells cannot inactivate the host response against donor class II alloantigens. Finally, donor CD4 cells and CD8 cells were equivalently effective for preventing rejection of F1 marrow in parental recipients, suggesting that veto activity is not restricted solely to the CD8 subset of murine T cells. A veto mechanism could enable donor T cells to prevent allogeneic marrow graft rejection without causing GVHD.

T Cell Receptor Gene Transfer to Produce MHC Class I-Restricted CD4 Helper T Cells: Implications for Immunotherapy of Leukaemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5262-5262
Author(s):  
Emma Morris ◽  
Aristotle Tsallios ◽  
Gavin Bendle ◽  
Shao-an Xue ◽  
Hans Stauss
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd4 T Cells ◽  
Tumour Cells ◽  
Class I ◽  
Helper T Cells ◽  
Specific Response ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Irrelevant Peptide

Abstract CD4 helper T cells play a critical role in the anti-tumour immune response. Cytokines secreted by CD4 T cells can have a direct effect on tumour cells and provide help for CTL priming and effector function. In this study we tested if it was possible to generate MHC class I-restricted helper T cells by retroviral TCR gene transfer into CD4 lymphocytes. Methods: We used a TCR (utilising V11) that recognises the influenza virus A nucleoprotein (NP366–379) peptide in the context of murine Db MHC class I. Murine splenocytes were isolated from C57BL/6 mice (H2b) and activated with conconavalin A and IL-7, and after 48 hours transduced with the pMX-TCR-IRES-TCR retroviral vector. The transduced splenocytes were then cultured in the presence of IL2 for a further 48 hours before staining with anti-murine CD4, CD8 and V11 antibodies and sorting into CD4+ V11+ and CD8+ V11+ populations. Sorted cells were expanded for a further 48–72 hours prior to functional assays. Functional Assays: Purified TCR-transduced (TCR-Td) CD8+ cells and purified TCR-Td CD4+ cells were tested for IFN secretion in response to dendritic cells (DCs) pulsed with NP peptide, an irrelevant peptide (pMDM100) or no peptide. Further experiments examined IFN secretion in response to peptide-loaded tumour cells (EL4 murine lymphoma cells) or transfected tumour cells expressing NP endogenously. Secretion of IFN was measured by ELISA. Results: (1) Antigen-specific IFN secretion was observed by both CD8+ (100% purity) and CD4+ cells (99.93% purity) expressing the class I-restricted TCR when incubated with peptide-loaded DCs. When tested with no peptide or irrelevant peptide, no IFN secretion was observed. The CD8+ cells were more sensitive, recognizing lower concentrations of peptide (10pM) than CD4+ cells (100pM). With peptide-coated EL4 tumour cells as stimulator cells, CD8+ cells showed a peptide-specific response. In contrast, the TCR-Td CD4+ cells were only able to elicit a weak peptide-specific response. Similarly, TCR-Td CD8+ cells were able to recognise NP transfected EL4 tumour cells (EL4NP68), whereas the CD4+ cells were unable to. However, the addition of syngeneic DCs restored the CD4+ cell response to NP transfected EL4 tumour cells to one equivalent to that seen with the TCR-Td CD8+ populations (Table 1). Summary: We have demonstrated that it is feasible to generate MHC class I-restricted CD4+ helper T cells, that are specific for peptide epitopes presented in the context of MHC class I. The CD4+ T cells can recognise antigen-expressing tumour cells in the presence of professional APC, such as DCs. The mechanism by which APC restore tumour recognition may involve trans-costimulation or cross presentation. The data suggest that class I-restricted CD4+ T cells may be able to contribute to enhanced anti-tumour immunity. αββββγγγγγβ γIFN Secretion (ng/ml) After Stimulation with DCs or Tumour Cells T Cell (Responder Cell) Stimulator Cell/s No Peptide NP (100nM) pMDM100 (100nM) Abbreviations: ND not done; DC, EL4 and EL4NP68 as indicated in text. TCR-Td CD8+ DCs 0.1 163.2 0.7 TCR-Td CD8+ EL4 0.1 19.9 0.2 TCR-Td CD8+ EL4NP68 16.6 ND ND TCR-Td CD8+ EL4NP68 + DCs 31.2 ND ND TCR-Td CD4+ DCs 0.1 163.9 0.2 TCR-Td CD4+ EL4 0.1 0.8 0.0 TCR-Td CD4+ EL4NP68 0.2 ND ND TCR-Td CD4+ EL4NP68 + DCs 25.3 ND ND

CD4 Cells Engineered to Express an MHC Class I Restricted TCR Can Rescue CD8 Cells Tolerized to Tumour-Associated Antigens

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 952-952
Author(s):  
Sara Ghorashian ◽  
Ben Carpenter ◽  
Angelika Holler ◽  
Emma Nicholson ◽  
Maryam Ahmadi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Class I ◽  
Target Cells ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Cognate Antigen ◽  
Cd4 Help

Abstract Abstract 952 Background: The efficacy of T cell therapies for cancer may be limited when targeting tumour-associated antigens (TAA) which are also self-antigens. Ongoing exposure to TAA on normal cells may lead to tolerance via anergy or exhaustion of antigen-specific T cells. Methods: We have designed a model of tolerance to TAA in which T cell receptor (TCR)-transduced CD8 T cells recognise pMDM2, a TAA that is also a ubiquitous self-antigen. CD8+ T cells were transduced with pMDM2-specific TCR (MDM-CD8) and transferred to sub-lethally irradiated B6 mice that express pMDM2 in the context of MHC Class I (H2-Kb). MDM-CD8 cells are detectable 4 weeks after transfer but show defective in vivo killing of target cells pulsed with MDM2 peptide. We have used this model to determine the mechanism of tolerance and to evaluate whether tolerant CD8+ T cells can be rescued by CD4 help. Results: To determine whether tolerance of MDM-CD8 cells was dependent upon recognition of cognate antigen, we transferred MDM-CD8 cells into mice of a different MHC background (BALB/c) which lack H2-Kb required for presentation of the TCR-recognised MDM2 peptide. When BALB/c MDM-CD8 cells were transferred to BALBc hosts their functions were preserved and they retained efficient antigen-specific cytolysis. To determine whether tolerance could be modified by provision of CD4+ T cell help, we co-transferred MDM-CD8 with transgenic OT-II CD4+ cells. OT-II cells were primed with dendritic cells (DCs) loaded with cognate pOVA323-339 or irrelevant peptide. When activated through their TCR, OT-II cells increased both the frequency of MDM2-specific CD8 cells and their cytotoxic functions, indicating that CD4 help can overcome CD8 tolerance to TAA. Ineffective antigen presentation to CD4 cells and lack of known MHC class II-restricted TAA are major limitations to providing CD4 help in T cell therapy for cancer. We therefore tested whether transfer of the MHC Class I-restricted MDM2 TCR into CD4 cells could provide help upon transfer to antigen-expressing hosts. Co-transfer of MDM2-TCR-transduced CD4 cells with CD8 cells improved antigen-specific killing of target cells when compared to single transfer of either TCR-transduced CD8 or CD4 cells. Conclusion: CD4 cells rendered capable of responding to an MHC class I restricted TAA by TCR transfer can rescue tolerance developing in a CD8 population with the same specificity. This is potentially a novel way to circumvent defective immune responses arising in adoptively transferred effector cells due to prolonged exposure to cognate antigen on normal host cells. Disclosures: Stauss: Cell Medica: Scientific Advisor Other.

MHC Sınıf I ve MHC Sınıf II Gen Düzenlenmesi

2020 ◽  
Vol 8 (3) ◽  
pp. 144-156
Author(s):  
Şule KARATAŞ ◽  
Fatma SAVRAN OĞUZ
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Gene Regulation ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Class I ◽  
Mhc Molecules ◽  
Class Ii Mhc ◽  
Regulation Mechanisms

Introduction: Peptides obtained by processing intracellular and extracellular antigens are presented to T cells to stimulate the immune response. This presentation is made by peptide receptors called major histocompatibility complex (MHC) molecules. The regulation mechanisms of MHC molecules, which have similar roles in the immune response, especially at the gene level, have significant differences according to their class. Objective: Class I and class II MHC molecules encoded by MHC genes on the short arm of the sixth chromosome are peptide receptors that stimulate T cell response. These peptides, which will enable the recognition of the antigen from which they originate, are loaded into MHC molecules and presented to T cells. Although the principles of loading and delivering peptides are similar for both molecules, the peptide sources and peptide loading mechanisms are different. In addition, class I molecules are expressed in all nucleated cells while class II molecules are expressed only in Antigen Presentation Cells (APC). These differences; It shows that MHC class I is not expressed by exactly the same transcriptional mechanisms as MHC class II. In our article, we aimed to compare the gene expressions of both classes and reveal their similarities and differences. Discussion and Conclusion: A better understanding of the transcriptional mechanisms of MHC molecules will reveal the role of these molecules in diseases more clearly. In our review, we discussed MHC gene regulation mechanisms with presence of existing informations, which is specific to the MHC class, for contribute to future research. Keywords: MHC class I, MHC class II, MHC gene regulation, promoter, SXY module, transcription

Human T Cells with Distinct Specificities Mediate Graft-Versus-Leukemia Reactivity and Xenogeneic Graft-Versus-Host Disease in a NOD/Scid Mouse Model for Human Acute Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1330-1330
Author(s):  
Sanja Stevanovic ◽  
Bart Nijmeijer ◽  
Marianke LJ Van Schie ◽  
Roelof Willemze ◽  
Marieke Griffioen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Class I ◽  
T Cell Clones ◽  
Cell Clones ◽  
Human T Cells

Abstract Abstract 1330 Poster Board I-352 Immunodeficient mice inoculated with human leukemia can be used as a model to investigate Graft-versus-Leukemia (GvL) effects of donor lymphocyte infusions (DLIs). In addition to GvL reactivity, treatment with DLI induces xenogeneic Graft-versus-Host Disease (GvHD) in mice, characterized by pancytopenia and weight loss. In patients treated with DLI for relapsed or residual leukemia after allogeneic stem cell transplantation, immune responses against non-leukemic cells may also cause GvHD. It has been suggested that GvL reactivity and GvHD, which co-develop in vivo, can be separated and that distinct T cells exist with the specific capacity to mediate GvL reactivity or GvHD. Since adoptive T cell transfer models that allow analysis of separation of GvL and GvHD are rare, we aimed to establish whether GvL reactivity and xenogeneic GvHD could be separated using our model of human leukemia-engrafted NOD/scid mouse after treatment with human donor T cells. In this study, non-conditioned NOD/scid mice engrafted with primary human acute lymphoblastic leukemic cells were treated with CD3+ DLI. Established tumors were effectively eliminated by emerging human T cells, but also induced xenogeneic GvHD. Flowcytometric analysis demonstrated that the majority of emerging CD8+ and CD4+ T cells were activated (HLA-DR+) and expressed an effector memory phenotype (CD45RA-CD45RO+CCR7-). To investigate whether GvL reactivity and xenogeneic GvHD were mediated by the same T cells showing reactivity against both human leukemic and murine cells, or displaying distinct reactivity against human leukemic and murine cells, we clonally isolated and characterized the T cells during the GvL response and xenogeneic GvHD. T cell clones were analyzed for reactivity against primary human leukemic cells and primary NOD/scid hematopoietic (BM and spleen cells) and non-hematopoietic (skin fibroblasts) cells in IFN-g ELISA. Isolated CD8+ and CD4+ T cell clones were shown to recognize either human leukemic or murine cells, indicating that GvL response and xenogeneic GvHD were mediated by different human T cells. Flowcytometric analysis demonstrated that all BM and spleen cells expressed MHC class I, whereas only 1-3 % of the cells were MHC class II +. Primary skin fibroblasts displayed low MHC class I and completely lacked MHC class II expression. Xeno-reactive CD8+ T cell clones were shown to recognize all MHC class I + target cells and xeno-reactive CD4+ T cells clones displayed reactivity only against MHC class II + target cells. To determine the MHC restriction of xeno-reactive T cell clones, NOD/scid bone marrow (BM) derived dendritic cells (DC) expressing high levels of murine MHC class I and class II were tested for T cell recognition in the presence or absence of murine MHC class I and class II monoclonal antibodies in IFN-g ELISA. Xeno-reactive CD8+ T cell clones were shown to be MHC class I (H-2Kd or H-2Db) restricted, whereas xeno-reactive CD4+ T cell clones were MHC class II (I-Ag7) restricted, indicating that xeno-reactivity reflects genuine human T cell response directed against allo-antigens present on murine cells. Despite production of high levels of IFN-gamma, xeno-reactive CD8+ and CD4+ T cell clones failed to exert cytolytic activity against murine DC, as determined in a 51Cr-release cytotoxicity assay. Absence of cytolysis by CD8+ T cell clones, which are generally considered as potent effector cells, may be explained by low avidity interaction between human T cells and murine DC, since flowcytometric analysis revealed sub-optimal activation of T cells as measured by CD137 expression and T cell receptor downregulation upon co-culture with murine DC, and therefore these results indicate that xenogeneic GvHD in this model is likely to be mediated by cytokines. In conclusion, in leukemia-engrafted NOD/scid mice treated with CD3+ DLI, we show that GvL reactivity and xenogeneic GvHD are mediated by separate human T cells with distinct specificities. All xeno-reactive T cell clones showed genuine recognition of MHC class I or class II associated allo-antigens on murine cells similar as GvHD-inducing human T cells. These data suggest that our NOD/scid mouse model of human acute leukemia may be valuable for studying the effectiveness and specificity of selectively enriched or depleted T cells for adoptive immunotherapy. Disclosures: No relevant conflicts of interest to declare.

Sialoadhesin-Positive Host Macrophages Play an Essential Role in Graft-Versus-Leukemia Reactivity in Mice

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4375-4386 ◽  
Author(s):  
Susanne Müerköster ◽  
Marian Rocha ◽  
Paul R. Crocker ◽  
Volker Schirrmacher ◽  
Victor Umansky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Class I ◽  
Peptide Epitope ◽  
Peptide Epitopes ◽  
Graft Versus Leukemia

We recently established an effective immune T-cell–mediated graft-versus-leukemia (GVL) murine model system in which complete tumor remissions were achievable even in advanced metastasized cancer. We now describe that this T-cell–mediated therapy is dependent on host macrophages expressing the lymphocyte adhesion molecule sialoadhesin (Sn). Depletion of Kupffer cells in tumor-bearing mice during adoptive immunotherapy (ADI) or the treatment of these animals with anti-Sn monoclonal antibodies led to complete or partial inhibition of the immune T-cell–mediated therapeutic effect. Furthermore, Sn+ host macrophages in livers formed clusters during ADI with donor CD8 T cells. To test for a possible antigen presentation function of these macrophages, we used as an in vitro model the antigen β-galactosidase for which a dominant major histocompatibility complex (MHC) class I Ld-restricted peptide epitope is known to be recognized by specific CD8 cytotoxic T lymphocytes (CTL). We demonstrate that purified Sn+ macrophages can process exogenous β-galactosidase and stimulate MHC class I peptide-restricted CTL responses. Thus, Sn+ macrophages, which are significantly increased in the liver after ADI, may process tumor-derived proteins via the MHC class I pathway as well as via the MHC class II pathway, as shown previously, and present respective peptide epitopes to CD8 as well as to CD4 immune T cells, respectively. The synergistic interactions observed before between immune CD4 and CD8 T cells during ADI could thus occur in the observed clusters with Sn+ host macrophages.

Expansion of CD8+ Cytotoxic T Cells in vitro and in vivo Using MHC Class I Tetramers

Tumor Biology ◽  
2007 ◽  
Vol 28 (2) ◽  
pp. 70-76 ◽  
Author(s):  
Philip Savage ◽  
Maggie Millrain ◽  
Sofia Dimakou ◽  
Justin Stebbing ◽  
Julian Dyson
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cytotoxic T Cells ◽  
Class I

Sialoadhesin-Positive Host Macrophages Play an Essential Role in Graft-Versus-Leukemia Reactivity in Mice

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4375-4386 ◽  
Author(s):  
Susanne Müerköster ◽  
Marian Rocha ◽  
Paul R. Crocker ◽  
Volker Schirrmacher ◽  
Victor Umansky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Class I ◽  
Peptide Epitope ◽  
Peptide Epitopes ◽  
Graft Versus Leukemia

Abstract We recently established an effective immune T-cell–mediated graft-versus-leukemia (GVL) murine model system in which complete tumor remissions were achievable even in advanced metastasized cancer. We now describe that this T-cell–mediated therapy is dependent on host macrophages expressing the lymphocyte adhesion molecule sialoadhesin (Sn). Depletion of Kupffer cells in tumor-bearing mice during adoptive immunotherapy (ADI) or the treatment of these animals with anti-Sn monoclonal antibodies led to complete or partial inhibition of the immune T-cell–mediated therapeutic effect. Furthermore, Sn+ host macrophages in livers formed clusters during ADI with donor CD8 T cells. To test for a possible antigen presentation function of these macrophages, we used as an in vitro model the antigen β-galactosidase for which a dominant major histocompatibility complex (MHC) class I Ld-restricted peptide epitope is known to be recognized by specific CD8 cytotoxic T lymphocytes (CTL). We demonstrate that purified Sn+ macrophages can process exogenous β-galactosidase and stimulate MHC class I peptide-restricted CTL responses. Thus, Sn+ macrophages, which are significantly increased in the liver after ADI, may process tumor-derived proteins via the MHC class I pathway as well as via the MHC class II pathway, as shown previously, and present respective peptide epitopes to CD8 as well as to CD4 immune T cells, respectively. The synergistic interactions observed before between immune CD4 and CD8 T cells during ADI could thus occur in the observed clusters with Sn+ host macrophages.

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