Mature murine megakaryocytes present antigen-MHC class I molecules to T cells and transfer them to platelets

Key Points Megakaryocytes process and present endogenous/exogenous antigens on MHC class I molecules to activate CD8+ T cells. Megakaryocytes can transfer MHC class I molecules loaded with foreign antigen to proplatelets in vitro.

Download Full-text

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

Blood ◽

10.1182/blood.v93.12.4375.412k32_4375_4386 ◽

1999 ◽

Vol 93 (12) ◽

pp. 4375-4386 ◽

Cited By ~ 1

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.

Download Full-text

Constitutive versus Activation-dependent Cross-Presentation of Immune Complexes by CD8+ and CD8− Dendritic Cells In Vivo

Journal of Experimental Medicine ◽

10.1084/jem.20020295 ◽

2002 ◽

Vol 196 (6) ◽

pp. 817-827 ◽

Cited By ~ 230

Author(s):

Joke M.M. den Haan ◽

Michael J. Bevan

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mhc Class I ◽

Cd8 T Cells ◽

Immune Complexes ◽

Class I ◽

Cross Presentation ◽

Deficient Mice ◽

Mhc Class I Molecules

Murine splenic dendritic cells (DCs) can be divided into two subsets based on CD8α expression, but the specific role of each subset in stimulation of T cells is largely unknown. An important function of DCs is the ability to take up exogenous antigens and cross-present them in the context of major histocompatibility complex (MHC) class I molecules to CD8+ T cells. We previously demonstrated that, when cell-associated ovalbumin (OVA) is injected into mice, only the CD8+ DC subset cross-presents OVA in the context of MHC class I. In contrast to this selectivity with cell-associated antigen, we show here that both DC subsets isolated from mice injected with OVA/anti-OVA immune complexes (OVA-IC) cross-present OVA to CD8+ T cells. The use of immunoglobulin G Fc receptor (FcγR) common γ-chain–deficient mice revealed that the cross-presentation by CD8− DCs depended on the expression of γ-chain–containing activating FcγRs, whereas cross-presentation by CD8+ DCs was not reduced in γ-chain–deficient mice. These results suggest that although CD8+ DCs constitutively cross-present exogenous antigens in the context of MHC class I molecules, CD8− DCs only do so after activation, such as via ligation of FcγRs. Cross-presentation of immune complexes may play an important role in autoimmune diseases and the therapeutic effect of antitumor antibodies.

Download Full-text

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

Blood ◽

10.1182/blood.v93.12.4375 ◽

1999 ◽

Vol 93 (12) ◽

pp. 4375-4386 ◽

Cited By ~ 34

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.

Download Full-text

Nitrosylation of Platelet MHC Class I Molecules Directs Their Movement into the Immunosuppressive MHC Class I Processing Pathway within Antigen Presenting Cells.

Blood ◽

10.1182/blood.v104.11.837.837 ◽

2004 ◽

Vol 104 (11) ◽

pp. 837-837

Author(s):

John W. Semple ◽

Edwin R. Speck ◽

John Freedman

Keyword(s):

Immune Response ◽

T Cells ◽

Mhc Class I ◽

Cd8 T Cells ◽

Brefeldin A ◽

Antigen Presenting Cells ◽

Class I ◽

Antigen Presenting ◽

Platelet Transfusions

Abstract Previous studies have demonstrated that recipient mice require the production of nitric oxide (NO) within their antigen presenting cells (APC) in order to generate IgG anti-donor immunity against allogeneic platelet transfusions. NO has a complex biochemistry and several of its conjurors could be involved in this response; the most obvious is peroxynitrite (ONOO-) generated by the spontaneous combination of NO and superoxide (O2•−). ONOO- is a potent oxidant that can spontaneously nitrosylate lysine and tyrosine residues in proteins within the phagolysosome. To address the role of ONOO- in platelet immunity, we transfused GP91 PHOX knockout mice that lack the ability to produce O2•− and thus ONOO-. Results show that when wild type C57BL/6 mice were transfused with allogeneic BALB/c platelets, they developed a weak IgG anti-donor antibody response by the fifth transfusion. In contrast, PHOX KO mice generated IgG anti-donor antibodies by the 2nd transfusion and their IgG anti-donor antibody titres were significantly higher than the WT recipients. This suggested that ONOO- and protein nitrosylation may be linked with an immunosuppressive event within the recipient. This was confirmed by demonstrating that in vitro nitrosylation of platelet antigens with the ONOO- donor SIN-1 inhibited the ability of the platelets to mount an IgG immune response when transfused into allogeneic recipients. Nitrosylated platelet antigen trafficking within recipient APC was assessed by using adherent macrophages and various inhibitors of processing. When adherent APC were pulsed with nitrosylated platelet antigens in the presence of either Brefeldin A or proteosome inhibitors, IgG anti-platelet immunity against the platelets was restored. Furthermore, the IgG immunity could also be rescued against the nitrsosylated platelets if the recipients were first depleted of CD8+ T cells by injection of a monoclonal antibody. These results suggest that if platelet antigens are nitrosylated within antigen presenting cells, they are preferentially shunted to the MHC class I processing pathway and presented to CD8+ T cells that suppress the IgG immune response. Thus, it appears that reactive oxygen species act as intracellular regulators that determine whether a productive IgG immune response against platelet transfusions will occur.

Download Full-text

Cd8+ but Not Cd8− Dendritic Cells Cross-Prime Cytotoxic T Cells in Vivo

Journal of Experimental Medicine ◽

10.1084/jem.192.12.1685 ◽

2000 ◽

Vol 192 (12) ◽

pp. 1685-1696 ◽

Cited By ~ 889

Author(s):

Joke M.M. den Haan ◽

Sophie M. Lehar ◽

Michael J. Bevan

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mhc Class I ◽

Cytotoxic T Lymphocyte ◽

Cytotoxic T Cells ◽

Class I ◽

Specific Subset ◽

Mhc Class I Molecules

Bone marrow–derived antigen-presenting cells (APCs) take up cell-associated antigens and present them in the context of major histocompatibility complex (MHC) class I molecules to CD8+ T cells in a process referred to as cross-priming. Cross-priming is essential for the induction of CD8+ T cell responses directed towards antigens not expressed in professional APCs. Although in vitro experiments have shown that dendritic cells (DCs) and macrophages are capable of presenting exogenous antigens in association with MHC class I, the cross-presenting cell in vivo has not been identified. We have isolated splenic DCs after in vivo priming with ovalbumin-loaded β2-microglobulin–deficient splenocytes and show that they indeed present cell-associated antigens in the context of MHC class I molecules. This process is transporter associated with antigen presentation (TAP) dependent, suggesting an endosome to cytosol transport. To determine whether a specific subset of splenic DCs is involved in this cross-presentation, we negatively and positively selected for CD8− and CD8+ DCs. Only the CD8+, and not the CD8−, DC subset demonstrates cross-priming ability. FACS® studies after injection of splenocytes loaded with fluorescent beads showed that 1 and 0.6% of the CD8+ and the CD8− DC subsets, respectively, had one or more associated beads. These results indicate that CD8+ DCs play an important role in the generation of cytotoxic T lymphocyte responses specific for cell-associated antigens.

Download Full-text

The natural immune response to inhaled soluble protein antigens involves major histocompatibility complex (MHC) class I-restricted CD8+ T cell-mediated but MHC class II-restricted CD4+ T cell-dependent immune deviation resulting in selective suppression of immunoglobulin E production.

Journal of Experimental Medicine ◽

10.1084/jem.178.3.889 ◽

1993 ◽

Vol 178 (3) ◽

pp. 889-899 ◽

Cited By ~ 223

Author(s):

C McMenamin ◽

P G Holt

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class I ◽

Mhc Class Ii ◽

Cd8 T Cells ◽

Immunoglobulin E ◽

Cd8 T Cell ◽

T Cell Response ◽

Class I

The immunological basis for atopy is currently ascribed to an inherent bias in the CD4+ T cell response to nonreplicating antigens presented at mucosal surfaces, resulting in dominance of the T helper 2 (Th2) interleukin 4 (IL-4)-producing phenotype, which favors IgE production. In contrast, the "normal" response to such antigens involves a predominance of interferon gamma (IFN-gamma)-producing Th1 clones. This difference has been suggested to be the result of active selection in atopics for Th2 (and hence against Th1) clones at the time of initial antigen presentation. In the study below, we demonstrate that the natural immune response to inhaled protein antigens, particularly in animals expressing the low immunoglobulin E (IgE) responder phenotype, includes a major histocompatibility complex (MHC) class I-restricted CD8+ T cell component, the appearance of which is associated with active suppression of IgE antibody production. Thus, continued exposure of rats to aerosolized ovalbumin (OVA) antigen elicits a transient IgE response, that is terminated by the onset of a state of apparent "tolerance" to further challenge, and this tolerant state is transferable to naive animals with CD8+ T cells. Kinetic studies on in vitro T cell reactivity in these aerosol-exposed rats demonstrated biphasic CD4+ Th2 responses which terminated, together with IgE antibody production, and coincident with the appearance of MHC class I-restricted OVA-specific IFN-gamma-producing CD8+ T cells. However, the latter were not autonomous in vitro and required a source of exogenous IL-2 for initial activation, which in CD(8+)-enriched splenocyte cultures could be provided by small numbers of contaminating OVA-specific CD4+ T cells. This represents the first formal evidence for the induction of an MHC class I-restricted T cell response to natural mucosal exposure to an inert protein antigen, and is consistent with a growing literature demonstrating sensitization of MHC class I-restricted CD8+ T cells by deliberate immunization with soluble proteins. We suggest that crossregulation of MHC class II-restricted CD4+ T cells via cytokine signals generated in parallel CD8+ T cell responses represents a covert and potentially important selection pressure that can shape the nature of host responses to nonreplicating antigens presented at mucosal surfaces.

Download Full-text

Expansion and Function of CD8+T Cells Expressing Ly49 Inhibitory Receptors Specific for MHC Class I Molecules

The Journal of Immunology ◽

10.4049/jimmunol.173.6.3773 ◽

2004 ◽

Vol 173 (6) ◽

pp. 3773-3782 ◽

Cited By ~ 22

Author(s):

Nicolas Anfossi ◽

Scott H. Robbins ◽

Sophie Ugolini ◽

Philippe Georgel ◽

Kasper Hoebe ◽

...

Keyword(s):

T Cells ◽

Mhc Class I ◽

Cd8 T Cells ◽

Class I ◽

Inhibitory Receptors ◽

And Function ◽

Mhc Class I Molecules

Download Full-text

Cytolytic responses: cadherins put out the fire

Journal of Experimental Medicine ◽

10.1084/jem.20052559 ◽

2006 ◽

Vol 203 (2) ◽

pp. 261-264 ◽

Cited By ~ 19

Author(s):

Marco Colonna

Keyword(s):

T Cells ◽

Mhc Class I ◽

Cd8 T Cells ◽

Class I ◽

Cytotoxic Lymphocytes ◽

Intracellular Pathogens ◽

Cell Recognition ◽

Cytotoxic Cells ◽

Mhc Class I Molecules ◽

Response Activation

Cytotoxic lymphocytes, such as natural killer (NK) cells and CD8+ T cells, provide an essential defense against intracellular pathogens and tumors. During target cell recognition, these cells receive both activating and inhibitory signals. The cell must evaluate these opposing signals and determine the appropriate response: activation or inhibition. Classically, inhibitory signals are mediated by receptors that recognize MHC class I molecules (1). But recent studies, including one in this issue, suggest that MHC class I-independent inhibitory signals can also result in inhibition of cytotoxic cells.

Download Full-text