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Biomedical subjects

Christian Münz

Publications and source records attributed to Christian Münz.

At least 19 recordsLinked to original sources
PubMed2007

Immune surveillance via self digestion.

The adaptive immune system is orchestrated by CD4+ T cells. These cells detect peptides presented on Major Histocompatibility Complex (MHC) class II molecules, which are loaded in late endosomes with products of lysosomal proteolysis. One pathway by which proteins gain access to degradation in lysosomes is macroautophagy. We recently showed that constitutive macroautophagy can be detected in cells relevant for the immune system, including dendritic cells. In these antigen presenting cells, autophagosomes frequently fused with MHC class II antigen loading compartments and targeting of Influenza matrix protein 1 (MP1) for macroautophagy enhanced MHC class II presentation to MP1-specific CD4+ T cell clones up to 20 fold. Our findings indicate that macroautophagy is a constitutive and efficient pathway of antigen delivery for MHC class II presentation. We suggest that this pathway samples intracellular proteins for immune surveillance and induction of tolerance in CD4+ T cells, and could be targeted for improved MHC class II presentation of vaccine antigens.

Antigen Presentation↗
PubMed2006

Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes.

Major histocompatibility complex (MHC) class II molecules present products of lysosomal proteolysis to CD4(+) T cells. Although extracellular antigen uptake is considered to be the main source of MHC class II ligands, a few intracellular antigens have been described to gain access to MHC class II loading after macroautophagy. However, the general relevance and efficacy of this pathway is unknown. Here we demonstrated constitutive autophagosome formation in MHC class II-positive cells, including dendritic, B, and epithelial cells. The autophagosomes continuously fuse with multivesicular MHC class II-loading compartments. This pathway was of functional relevance, because targeting of the influenza matrix protein 1 to autophagosomes via fusion to the autophagosome-associated protein Atg8/LC3 led to strongly enhanced MHC class II presentation to CD4(+) T cell clones. We suggest that macroautophagy constitutively and efficiently delivers cytosolic proteins for MHC class II presentation and can be harnessed for improved helper T cell stimulation.

Antigen Presentation↗
PubMed2006

Distinct memory CD4+ T-cell subsets mediate immune recognition of Epstein Barr virus nuclear antigen 1 in healthy virus carriers.

CD4+ T cells, specific for transforming latent infection with the Epstein Barr virus (EBV), consistently recognize the nuclear antigen 1 of EBV (EBNA1). EBNA1-specific effector CD4+ T cells are primarily T-helper 1 (TH1) polarized. Here we show that most healthy EBV carriers have such IFN-secreting EBNA1-specific CD4+ T cells at a frequency of 0.03% of circulating CD4+ T cells. In addition, healthy carriers have a large pool of CD4+ T cells that proliferated in response to EBNA1 and consisted of distinct memory-cell subsets. Despite continuous antigen presence due to persistent EBV infection, half of the proliferating EBNA1-specific CD4+ T cells belonged to the central-memory compartment (TCM). The remaining EBNA1-specific CD4+ T cells displayed an effector-memory phenotype (TEM), of which a minority rapidly secreted IFN upon stimulation with EBNA1. Based on chemokine receptor analysis, all EBNA1-specific TCM CD4+ T cells were TH1 committed. Our results suggest that protective immune control of chronic infections, like EBV, includes a substantial reservoir of TCM CD4+ TH1 precursors, which continuously fuels TH1-polarized effector cells.

Antigens, Viral↗
PubMed2006

Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis.

Epidemiological studies consistently demonstrate that patients with multiple sclerosis are almost universally infected with Epstein-Barr virus (EBV) and that the risk of developing the disease increases with the level of EBV-specific antibody titers. The EBV-encoded nuclear antigen-1 (EBNA1) maintains the viral episome in replicating infected human B cells, and EBNA1-specific CD4+ T cells have been identified as a crucial part of the EBV-specific immune control in healthy individuals. We studied 20 untreated EBV seropositive patients with multiple sclerosis and 20 healthy EBV carriers matched demographically and for the expression of multiple sclerosis-associated HLA-DR alleles for their immunological control of EBV latency at the level of EBNA1-specific T cells. Using 51 overlapping peptides covering the C-terminal of EBNA1 domain of EBNA1 (amino acids 400-641), peptide-specific CD4+ memory T cells in patients with multiple sclerosis were found to be strikingly elevated in frequency, showed increased proliferative capacity and an enhanced interferon-gamma production. In contrast to EBNA1, T-cell responses to three other latent and three other lytic immunodominant EBV antigens and human cytomegalovirus (HCMV) epitopes did not differ between patients and controls, indicating a distinct role for EBNA1-specific T-cell responses in multiple sclerosis. CD4+ T cells from healthy virus carriers preferentially recognized multiple epitopes within the centre part of the C-terminal, whereas the stimulatory epitopes in multiple sclerosis patients covered the entire sequence of this domain of EBNA1. Quantification of EBV viral loads in peripheral blood mononuclear cells (PBMC) by real-time polymerase chain reaction (PCR) showed higher levels of EBV copy numbers in some patients with multiple sclerosis, although the overall difference in viral loads was not statistically significant compared with healthy virus carriers. We suggest that the accumulation of highly antigen-sensitive EBNA1-specific Th1 cells in multiple sclerosis is capable of sustaining autoimmunity by cross-recognition of autoantigens or by TCR-independent bystander mechanisms.

Adult↗
PubMed2006

Virus-specific CD4+ T cells: ready for direct attack.

CD4+ T cells are classically thought to orchestrate adaptive immune responses. But recent studies demonstrate that they can also kill infected cells directly. A new paper shows that highly efficient processing of Epstein Barr virus (EBV) glycoproteins for presentation on MHC class II makes virus-transformed B cells susceptible to lysis by CD4+ T cells. Thus, antiviral vaccines should aim to stimulate both helper and cytolytic CD4+ T cells.

Animals↗
PubMed2006

Autophagy in innate and adaptive immunity against intracellular pathogens.

Autophagy delivers cytoplasmic constituents for lysosomal degradation. Recent studies have demonstrated that this pathway mediates resistance to pathogens and is targeted for immune evasion by viruses and bacteria. Lysosomal degradation products, including pathogenic determinants, are then surveyed by the adaptive immune system to elicit antigen-specific T cell responses. CD4(+) T helper cells have been shown to recognize nuclear and cytosolic antigens via presentation by major histocompatibility complex (MHC) class II molecules after autophagy. Furthermore, some sources of natural MHC class II ligands display characteristics of autophagy substrates, and autophagosomes fuse with late endosomes, in which MHC class II loading is thought to occur. Although MHC class II antigen processing via autophagy has so far mainly been described for professional antigen-presenting cells like B cells, macrophages, and dendritic cells, it might be even more important for cells with less endocytic potential, like epithelial cells, when these express MHC class II at sites of inflammation. Therefore, autophagy might contribute to immune surveillance of intracellular pathogens via MHC class II presentation of intracellular pathogen-derived peptides.

Adaptation, Physiological↗
PubMed2006

NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-gamma secretion.

Human secondary lymphoid tissues harbor NK cells that predominantly secrete cytokines in response to activation. Here, we demonstrate that these immunoregulatory NK cells assist in the Th1 polarization of primary immune responses, induced by dendritic cells. Tonsilar, but not peripheral blood NK cells enhanced the expansion of IFN-gamma-producing CD4+ T cells via their superior ability to produce IFN-gamma. Addition of IFN-gamma increased Th1 polarization while antibody blocking of this cytokine abolished NK cell-dependent Th1 polarization. Our data suggest that NK cells in secondary lymphoid organs assist priming of Th1 cells via cytokine secretion and this effect should be harnessed during vaccination against viruses and tumors.

Cell Differentiation↗
PubMed2006

Autophagy and antigen presentation.

CD4(+) T cells co-ordinate adaptive immunity and are required for immunological memory establishment and maintenance. They are thought to primarily recognize extracellular antigens, which are endocytosed, processed by lysosomal proteases and then presented on major histocompatibility complex (MHC) class II. However, recent studies have demonstrated that viral, tumour and autoantigens can gain access to this antigen presentation pathway from within cells by autophagy. This review will discuss the autophagic pathways that contribute to endogenous MHC class II antigen processing. Furthermore, potential characteristics of autophagy substrates, qualifying them to access these pathways, and regulation of autophagy will be considered. Finally, I will suggest how antigen presentation after autophagy might contribute to immune surveillance of infected and transformed cells.

Animals↗
PubMed2005

Dendritic cells expand Epstein Barr virus specific CD8+ T cell responses more efficiently than EBV transformed B cells.

Adoptive transfer of Epstein Barr virus (EBV) specific cytotoxic T lymphocytes (CTLs) has been successfully applied in the treatment of EBV associated post-transplant lymphoproliferative disease (PTLD). In most studies EBV transformed B cells (LCLs) have been used for the induction of EBV specific T cell lines. Application of this approach to other EBV associated tumors is difficult, because LCLs focus T cell expansion toward immunodominant EBV antigens that are not expressed in EBV associated Hodgkin's lymphoma and nasopharyngeal carcinoma. Therefore, we compared dendritic cells (DCs) with LCLs for CD8+ T cell stimulation against dominant and subdominant EBV antigens. DCs expanded tenfold more EBNA3A and LMP2 specific CD8+ T cells than LCL and also stimulated EBV specific CTL from PTLD patients. Both, DCs and LCLs stimulations led to the expansion of high affinity T cells, capable to target EBV transformed B cells. While LCLs and DCs expressed MHC class I and II products at similar levels, DCs showed a higher expression of costimulatory and adhesion molecules. This resulted in more efficient T cell conjugate formation with DCs than with LCLs. We propose the use of DCs for stimulation of EBV specific T cells in active or passive immunotherapy of EBV associated malignancies.

Antigens, Surface↗
PubMed2005

Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity.

Pathogen recognition by Toll-like receptors (TLRs) on dendritic cells (DCs) leads to DC maturation and the initiation of adaptive immunity. Recent studies have shown that innate lymphocytes--natural killer (NK), natural killer T (NKT), and gammadelta T cells--also trigger DC maturation. This interaction in turn expands and activates innate lymphocytes and initiates adaptive T cell immunity. Here, we comment on the evidence that these pathways are TLR independent and have the potential to respond to infection, malignancy, and immunotherapy.

Animals↗
PubMed2004

Endogenous MHC class II processing of a viral nuclear antigen after autophagy.

CD4+ T cells classically recognize antigens that are endocytosed and processed in lysosomes for presentation on major histocompatibility complex (MHC) class II molecules. Here, endogenous Epstein-Barr virus nuclear antigen 1 (EBNA1) was found to gain access to this pathway by autophagy. On inhibition of lysosomal acidification, EBNA1, the dominant CD4+ T cell antigen of latent Epstein-Barr virus infection, slowly accumulated in cytosolic autophagosomes. In addition, inhibition of autophagy decreased recognition by EBNA1-specific CD4+ T cell clones. Thus, lysosomal processing after autophagy may contribute to MHC class II-restricted surveillance of long-lived endogenous antigens including nuclear proteins relevant to disease.

Animals↗
PubMed2004

Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs.

Dendritic cells (DCs) are known to induce the growth and function of natural killer (NK) cells. Here, we address the capacity of DCs to interact with NK cells in human lymphoid organs and identify the role of specific DC-derived cytokines. We demonstrate that DCs colocalize with NK cells in the T cell areas of lymph nodes. In culture, DCs from either blood or spleen primarily stimulate the CD56(bright)CD16- NK cell subset, which is enriched in secondary lymphoid tissues. Blocking of IL-12 abolished DC-induced IFN-gamma secretion by NK cells, whereas membrane-bound IL-15 on DCs was essential for NK cell proliferation and survival. Maturation by CD40 ligation promoted the highest IL-15 surface presentation on DCs and led to the strongest NK cell proliferation induced by DCs. These results identify secondary lymphoid organs as a potential DC/NK cell interaction site and identify the distinct roles for DC-derived IL-12 and IL-15 in NK cell activation.

CD56 Antigen↗
PubMed2004

Mature myeloid dendritic cell subsets have distinct roles for activation and viability of circulating human natural killer cells.

Natural killer (NK) cells are important effectors of innate immunity. In contrast to many studies of interleukin-2 (IL-2)-activated NK cells, the physiologic requirements for stimulating resting NK cells have only recently received attention. Given the emerging variety of dendritic cell (DC) types and their division of labor for stimulating immunity, we compared the capacity of monocyte-derived DCs (moDCs) with that of CD34+ hematopoietic progenitor cell (HPC)-derived dermal-interstitial DCs (DDC-IDCs) and Langerhans cells (LCs) to stimulate resting NK cells. MoDCs, and to a lesser extent CD34+ HPC-derived DDC-IDCs, directly stimulate NK-cell proliferation, CD56 up-regulation, and cytotoxicity. LCs, on the contrary, require exogenous IL-2 or IL-12 to activate NK cells, but they can maintain resting NK-cell viability and sustain NK-cell proliferation induced by moDCs. LCs do not secrete bioactive IL-12p70 but do produce significantly higher concentrations of IL-15 and IL-18 than either of the other 2 DC types. Despite secretion of IL-15, LCs lack IL-15R-alpha for surface presentation of IL-15. This together with the deficiency of IL-12p70 undermines any direct NK-cell activation by LCs. Hence, the principal myeloid DCs differ in critical ways regarding the stimulation of NK and T lymphocytes and could be used or targeted accordingly in DC-based immunotherapies.

CD4-Positive T-Lymphocytes↗
PubMed2004

Mature human Langerhans cells derived from CD34+ hematopoietic progenitors stimulate greater cytolytic T lymphocyte activity in the absence of bioactive IL-12p70, by either single peptide presentation or cross-priming, than do dermal-interstitial or monocyte-derived dendritic cells.

The emerging heterogeneity of dendritic cells (DCs) mirrors their increasingly recognized division of labor at myriad control points in innate and acquired cellular immunity. We separately generated blood monocyte-derived DCs (moDCs), as well as Langerhans cells (LCs) and dermal-interstitial DCs (DDC-IDCs) from CD34(+) hematopoietic progenitor cells. Differential expression of CD11b, CD52, CD91, and the CD1 isoforms proved useful in distinguishing these three DC types. All mature DCs uniformly expressed comparable levels of HLA-DR, CD83, CD80, and CD86, and were potent stimulators of allogeneic T cells after exposure either to recombinant human CD40L trimer or a combination of inflammatory cytokines with PGE(2). moDCs, however, required 0.5-1 log greater numbers than LCs or DDC-IDCs to stimulate comparable T cell proliferation. Only moDCs secreted the bioactive heterodimer IL-12p70, and moDCs phagocytosed significantly more dying tumor cells than did either LCs or DDC-IDCs. LCs nevertheless proved superior to moDCs and DDC-IDCs in stimulating CTL against a recall viral Ag by presenting passively loaded peptide or against tumor Ag by cross-priming autologous CD8(+) T cells. LCs also secreted significantly more IL-15 than did either moDCs or DDC-IDCs, which is especially important to the generation of CTL. These findings merit further comparisons in clinical trials designed to determine the physiologic relevance of these distinctions in activity between LCs and other DCs.

Antigen Presentation↗
PubMed2004

Epstein-barr virus nuclear antigen 1: from immunologically invisible to a promising T cell target.

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)--the one EBV antigen that is expressed in all EBV-associated malignancies--has long been thought to go undetected by the cell-mediated immune system. However, recent studies show that EBNA1 can be presented to both CD4+ and CD8+ T cells, making it a potential new target for immunotherapy of EBV-related cancers.

Epstein-Barr Virus Nuclear Antigens↗
PubMed2004

The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic.

Natural killer cells are important cytolytic cells in innate immunity. We have characterized human NK cells of spleen, lymph nodes, and tonsils. More than 95% of peripheral blood and 85% of spleen NK cells are CD56(dim)CD16(+) and express perforin, the natural cytotoxicity receptors (NCRs) NKp30 and NKp46, as well as in part killer cell Ig-like receptors (KIRs). In contrast, NK cells in lymph nodes have mainly a CD56(bright)CD16(-) phenotype and lack perforin. In addition, they lack KIRs and all NCR expression, except low levels of NKp46. The NK cells of tonsils also lack perforin, KIRs, NKp30, and CD16, but partially express NKp44 and NKp46. Upon IL-2 stimulation, however, lymph node and tonsilar NK cells up-regulate NCRs, express perforin, and acquire cytolytic activity for NK-sensitive target cells. In addition, they express CD16 and KIRs upon IL-2 activation, and therefore display a phenotype similar to peripheral blood NK cells. We hypothesize that IL-2 can mobilize the NK cells of secondary lymphoid tissues to mediate natural killing during immune responses. Because lymph nodes harbor 40% and peripheral blood only 2% of all lymphocytes in humans, this newly characterized perforin(-) NK cell compartment in lymph nodes and related tissues probably outnumbers perforin(+) NK cells. These results also suggest secondary lymphoid organs as a possible site of NK cell differentiation and self-tolerance acquisition.

Cell Line, Transformed↗