MHC Class II-restricted Antigen Presentation Research Articles

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors.

Cancer immunotherapy critically depends on fitness of cytotoxic and helper Tcell responses. Dysfunctional cytotoxic Tcell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of Tcell dysfunction in the TME. We show here that major histocompatibility complex class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ Tcell states through increased chromatin accessibility and expression of Tox, a critical regulator of Tcell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ Tcells restricts myeloid-derived osteopontin that triggers a chronic activation of NFAT2 in tumor-reactive CD8+ Tcells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic Tcell states in brain tumors.

JAK1 signaling in dendritic cells promotes peripheral tolerance in autoimmunity through PD-L1-mediated regulatory Tcell induction.

Dendritic cells (DCs) induce peripheral Tcell tolerance, but cell-intrinsic signaling cascades governing their stable tolerogenesis remain poorly defined. Janus Kinase 1 (JAK1) transduces cytokine-receptor signaling, and JAK inhibitors (Jakinibs), including JAK1-specific filgotinib, break inflammatory cycles in autoimmunity. Here, we report in heterogeneous DC populations of multiple secondary lymphoid organs that JAK1 promotes peripheral Tcell tolerance during experimental autoimmune encephalomyelitis (EAE). Mice harboring DC-specific JAK1 deletion exhibit elevated peripheral CD4+ Tcell expansion, less regulatory Tcells (Tregs), and worse EAE outcomes, whereas adoptive DC transfer ameliorates EAE pathogenesis by inducing peripheral Tregs, programmed cell death ligand 1 (PD-L1) dependently. This tolerogenic program is substantially reduced upon the transfer of JAK1-deficient DCs. DC-intrinsic IFN-γ-JAK1-STAT1 signaling induces PD-L1, which is required for DCs to convert CD4+ Tcells into Tregs invitro and attenuated upon JAK1 deficiency and filgotinib treatment. Thus, DC-intrinsic JAK1 promotes peripheral tolerance, suggesting potential unwarranted DC-mediated effects of Jakinibs in autoimmune diseases.

MHC Class II Antigen Presentation by Lymphatic Endothelial Cells in Tumors Promotes Intratumoral Regulatory T cell-Suppressive Functions.

Several solid malignancies trigger lymphangiogenesis, facilitating metastasis. Tumor-associated lymphatic vessels significantly contribute to the generation of an immunosuppressive tumor microenvironment (TME). Here, we have investigated the ability of tumoral lymphatic endothelial cells (LEC) to function as MHC class II-restricted antigen-presenting cells in the regulation of antitumor immunity. Using murine models of lymphangiogenic tumors engrafted under the skin, we have shown that tumoral LECs upregulate MHC class II and the MHC class II antigen-processing machinery, and that they promote regulatory T-cell (Treg) expansion ex vivo. In mice with LEC-restricted lack of MHC class II expression, tumor growth was severely impaired, whereas tumor-infiltrating effector T cells were increased. Reduction of tumor growth and reinvigoration of tumor-specific T-cell responses both resulted from alterations of the tumor-infiltrating Treg transcriptome and phenotype. Treg-suppressive functions were profoundly altered in tumors lacking MHC class II in LECs. No difference in effector T-cell responses or Treg phenotype and functions was observed in tumor-draining lymph nodes, indicating that MHC class II-restricted antigen presentation by LECs was required locally in the TME to confer potent suppressive functions to Tregs. Altogether, our study suggests that MHC class II-restricted antigen-presenting tumoral LECs function as a local brake, dampening T cell-mediated antitumor immunity and promoting intratumoral Treg-suppressive functions.

The immunobiology of ubiquitin-dependent B cell receptor functions

MHC class II-restricted antigen presentation by dendritic cells is necessary for activation of naïve CD4 T cells, whereas class II-restricted antigen presentation by B lymphocytes and macrophages is important for the recruitment of CD4+ helper and regulatory T cells. Antigen presentation by B cells is also important for induction of T cell tolerance. B cells are unique among these three types of MHC class II-expressing antigen presenting cells (APC) as they constitutively express high levels of cell surface class II molecules and express a clonally restricted antigen specific receptor, the B cell receptor (BCR). Here, I review our current understanding of three major steps that underlie the processing and presentation of BCR-bound cognate antigen: (1) endocytosis of antigen-BCR (Ag-BCR) complexes, (2) Ag-BCR trafficking to intracellular antigen processing compartments and (3) generation of antigenic peptide-MHC class II complexes, with a particular focus on the role of BCR ubiquitination in each. I will highlight potential topics for future research and briefly discuss the impact of the cell biology of BCR-mediated antigen processing on the response of the B cell and T cell to the cell-cell interactions mediated by B cell-expressed peptide-class II complexes.

Heparan sulfates targeting increases MHC class I- and MHC class II-restricted antigen presentation and CD8+ T-cell response

Heparan sulfates (HS) are carbohydrate moieties of HS proteoglycans (HSPGs). They often represent alternative attachment points for proteins or microorganisms targeting receptors. HSPGs, which are ubiquitously expressed, thereby participate in numerous biological processes. We previously showed that MHC class II-restricted antigen presentation is increased when antigens are coupled to HS ligands, suggesting that HSPGs might contribute to adaptive immune responses. Here, we examined if HSPG targeting influences other aspects of immune responses. We found that coupling of an HS ligand to the antigen increases antigen presentation to CD4+ and CD8+ T-cells after antigen targeting to membrane immunoglobulins or to MHC-II molecules. Moreover, this increased stimulating capacity correlates with an enhanced CD8+ immune response in mice. Last, animals control more effectively the growth of Ova-expressing tumour cells when they are immunized with an Ova construct targeting HSPGs and MHC-II molecules. Our results indicate that ubiquitous molecules can influence both MHC class I- and MHC class II-restricted antigen presentation and behave as co-receptors during T-cell stimulation. Moreover, they suggest that tumour-antigens endowed with the ability to target both HSPGs and MHC-II molecules could be of value to increase CD8+ immune response and control tumour-growth, opening new perspectives for the design of highly immunogenic protein-based vaccines.

Abstract B047: Adequate Antigen Availability (AAA) in antitumor immunity: Definition and consequences for novel strategies of tumor prevention and antitumor treatment

Abstract Present immunopreventive and immunotherapeutic approaches against cancer suffer from the limitation of being not “sterilizing” procedures, as very poor protection against the tumor is obtained. Thus, newly conceived anti-tumor strategies of intervention are urgently needed. Here we introduce the concept of Adequate Antigen Availability (AAA) defined as the optimal tumor antigen dose and related antigen processing and MHC class II-restricted presentation necessary to trigger efficient tumor-specific TH cells (1). We will present results on a preventive anti-tumor vaccination system that consists in injecting tumor cells genetically modified to constitutively express MHC class II molecules by transfecting the MHC-II transcriptional activator CIITA. AAA is generated by the function of tumor's newly expressed MHC-II molecules to present tumor-associated antigens to tumor-specific CD4+ TH cells. We will show that tumor rejection against the CIITA-transfected neoplastic cells is brought about by the generation of persistent anti-tumor TH cell memory, responsible of protecting the animals from subsequent challenges with parental, untransfected tumor cells. This approach has been validated in tumor cells of different histotypic origin and of distinct MHC genotype (H-2d and H-2b). Importantly, the anti-tumor TH cell response modifies the tumor microenvironment, favouring the infiltration of CD4+ TH cells, CD8+ cytolytic T cells and granulocytes and dramatically reducing both intratumoral and lymphnode infiltration of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Thus the optimal initiation of the adaptive immune response, dictated by AAA, is sufficient to reorient the tumor microenvironment from a pro-tumor to an anti-tumor microenvironment. Our approach is, at present, applied to human clinical setting in hepatocellular carcinomas (2) whereby human tumor cells are rendered HLA class II-positive by CIITA genetic transfer with the aim to purify and sequence immunogenically relevant HLA class II-bound tumor–associated antigenic (TAA) peptides. In conjunction with similarly derived HLA class I-restricted TAA peptides, they will be the basis for the construction of a multi-peptide, multi-epitope vaccine that can target both CD4+ TH and CD8+ CTL anti-tumor responses.

MHC Class II-restricted antigen presentation by plasmacytoid dendritic cells drives proatherogenic T cell immunity.

Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and are important regulators of immuno-inflammatory diseases. However, their role in atherosclerosis remains elusive. Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Selective pDC deficiency in vivo was achieved using CD11c-Cre × Tcf4(-/flox) bone marrow transplanted into Ldlr(-/-) mice. Compared with control Ldlr(-/-) chimeric mice, CD11c-Cre × Tcf4(-/flox) mice had reduced atherosclerosis levels. To begin to understand the mechanisms by which pDCs regulate atherosclerosis, we studied chimeric Ldlr(-/-) mice with selective MHCII deficiency on pDCs. Significantly, these mice also developed reduced atherosclerosis compared with controls without reductions in pDC numbers or changes in conventional DCs. MHCII-deficient pDCs showed defective stimulation of apolipoprotein B100-specific CD4(+) T cells in response to native low-density lipoprotein, whereas production of interferon-α was not affected. Finally, the atheroprotective effect of selective MHCII deficiency in pDCs was associated with significant reductions of proatherogenic T cell-derived interferon-γ and lesional T cell infiltration, and was abrogated in CD4(+) T cell-depleted animals. This study supports a proatherogenic role for pDCs in murine atherosclerosis and identifies a critical role for MHCII-restricted antigen presentation by pDCs in driving proatherogenic T cell immunity.

MHC class II-restricted antigen presentation by plasmacytoid dendritic cells drive pro-atherogenic immunity

Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and are important regulators of immuno-inflammatory diseases. However, their role in atherosclerosis remains elusive. Antibody–mediated depletion of pDCs significantly alters atherosclerosis in mice but results and reported mechanisms have differed between studies. Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Partial but selective pDC deficiency was achieved using CD11c-Cre x Tcf4–/flox bone marrow transplanted into Ldlr–/– mice.

Oxidised low-density lipoproteins induce platelet adhesion, activation and spreading through novel CD36-tyrosine kinase/Rho kinase dependent signalling pathways

Oxidised low-density lipoproteins induce platelet adhesion, activation and spreading through novel CD36-tyrosine kinase/Rho kinase dependent signalling pathways

Boosting the MHC Class II-Restricted Tumor Antigen Presentation to CD4+ T Helper Cells: A Critical Issue for Triggering Protective Immunity and Re-Orienting the Tumor Microenvironment Toward an Anti-Tumor State

Although the existence of an immune response against tumor cells is well documented, the fact that tumors take off in cancer patients indicates that neoplastic cells can circumvent this response. Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease. When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome. We believe that the failure is mostly due to the inadequate triggering of the CD4+ T helper (TH) cell arm of the adaptive immunity, as TH cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells. In this review, we focus on novel strategies that by stimulating MHC class II-restricted activation of TH cells generate a specific and persistent adaptive immunity against the tumor. This point is of critical importance for both preventive and therapeutic anti-tumor vaccination protocols, because adaptive immunity with its capacity to produce specific, long-lasting protection and memory responses is indeed the final goal of vaccination. We will discuss data from our as well as other laboratories which strongly suggest that triggering a specific and persistent anti-tumor CD4+ TH cell response stably modify not only the tumor microenvironment but also tumor-dependent extratumor microenvironments by eliminating and/or reducing the blood-derived tumor infiltrating cells that may have a pro-tumor growth function such as regulatory CD4+/CD25+ T cells and myeloid-derived-suppressor cells. Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes.

The mannose receptor is expressed by olfactory ensheathing cells in the rat olfactory bulb

Complex carbohydrate structures are essential molecules of infectious bacteria, parasites, and host cells and are involved in cell signaling associated with immune responses, glycoprotein homeostasis, and cell migration. The uptake of mannose-tailed glycans is usually carried out by professional phagocytes to trigger MHC class I- and MHC class II-restricted antigen presentation or, alternatively, to end inflammation. We have detected the mannose receptor (MR) in cultured olfactory ensheathing cells (OECs), so we investigated by flow cytometry whether recently dissociated cells of the olfactory bulb (OB) nerve fiber layer (ONL) could bind a mannosylated ligand (fluorescein conjugate of mannosyl bovine serum albumin; Man/BSA-FITC) in a specific manner. In addition, we estimated the relative proportion of ONL OECs, microglia, and astrocytes, tagged by 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), by the B4 isolectin of Griffonia simplicifonia (IB4), and by glial fibrillary acidic protein (GFAP), respectively, that were Man/BSA-FITC(+) . We also determined by histochemistry and/or immunohistochemistry whether Man/BSA-FITC or an anti-MR antibody (anti-C-terminal MR peptide; anti-cMR) labeled OECs and/or parenchymal microglia. In addition, we confirmed by Western blot with the K1K2 (against the entire MR molecule) antibody that a band of about 180 kDA is expressed in the OB. Our findings are compatible with a prospective sentinel role of OECs against pathogens of the upper airways and/or damage-associated glycidic patterns as well as with homeostasis of OB mannosylated glycoproteins.

Metformin reduces gene expression of adipogenesis and inflammatory cytokines through the modulation of T cell priming in obese-induced Type II diabetic mice (P5063)

Abstract Inflammation is increasingly regarded as a key process underlying metabolic diseases in obese individuals where obese adipose tissue shows features characteristic of active local inflammation. Metformin is a biguanide derivative used in the treatment of T2D and one of the world's most widely prescribed drugs and have been suggested that metformin has anti-inflammatory properties. Here we show that metformin efficiently attenuates the metabolic disorder in DIO mice and suppresses MHC-restricted antigen presentation in dendritic cells. This study was to investigate the therapeutic effect of metformin on diabetic symptoms in DIO mice. Metformin decreased aipogenesis related gene, FAS, SCD-1, GPAT, SREBP1a, but also suppressed gene expression of innate cytokines than control mice. Metformin decreased both class I- and class II-restricted presentation of exogenous OVA in dendritic cells. Metformin also decreased expression of the co-stimulatory molecules, ICAM-1 and B7-1/-2, and MHC class I and II molecules but not phagocytic activity of DCs. Metformin decreased MHC class II-restricted exogenous antigen presentation in peritoneal macrophages in vivo. These results show that metformin attenuates immune responses followed by decreases MHC-restricted presentation of exogenous antigen in DCs via intracellular processing events. Theses finding suggest that modulation of the antigen presentation pathway could provide a novel means for regulating T cell responses in metabolic diseases.

Optimal MHC-II-restricted tumor antigen presentation to CD4+ T helper cells: the key issue for development of anti-tumor vaccines

Present immunoprevention and immunotherapeutic approaches against cancer suffer from the limitation of being not “sterilizing” procedures, as very poor protection against the tumor is obtained. Thus newly conceived anti-tumor vaccination strategies are urgently needed. In this review we will focus on ways to provide optimal MHC class II-restricted tumor antigen presentation to CD4+ T helper cells as a crucial parameter to get optimal and protective adaptive immune response against tumor. Through the description of successful preventive or therapeutic experimental approaches to vaccinate the host against the tumor we will show that optimal activation of MHC class II-restricted tumor specific CD4+ T helper cells can be achieved in various ways. Interestingly, the success in tumor eradication and/or growth arrest generated by classical therapies such as radiotherapy and chemotherapy in some instances can be re-interpreted on the basis of an adaptive immune response induced by providing suitable access of tumor-associated antigens to MHC class II molecules. Therefore, focussing on strategies to generate better and suitable MHC class II–restricted activation of tumor specific CD4+ T helper cells may have an important impact on fighting and defeating cancer.

Vaccinia virus A35R inhibits MHC class II antigen presentation

The Vaccinia virus gene A35R (Copenhagen designation) is highly conserved in mammalian-tropic poxviruses and is an important virulence factor, but its function was unknown. We show herein that A35 does not affect viral infectivity, apoptosis induction, or replication; however, we found that A35 significantly inhibited MHC class II-restricted antigen presentation, immune priming of T lymphocytes, and subsequent chemokine and cytokine synthesis. A35 localized to endosomes and reduced the amount of a model antigenic peptide displayed in the cleft of class II MHC. In addition, A35 decreased VV specific T cell responses in vivo. Thus, this is the first report identifying a function for the A35 protein in virulence as well as the first report identifying a VV gene that inhibits peptide antigen presentation.

Efficient uptake of mannosylated proteins by a human Schwann cell line.

Complex carbohydrate structures are essential molecules of infectious microbes and host cells, and are involved in cell signaling associated with inflammatory and immune responses. The uptake of mannose-tailed glycans is usually carried out by macrophages, dendritic cells (DCs), and other professional phagocytes to trigger MHC class I- and MHC class II-restricted antigen presentation, and to promote T cell effector responses. Since Schwann cells (SCs) have been proposed as immunocompetent cells, we investigated whether a human cell line (ST88-14 cells) could bind mannosylated ligands in a specific manner. The saturation of uptake of mannosylated molecules by ST88-14 cells and the internalization and distribution pathway of these ligands were tested by cytometry and confocal plus electron microscopy, respectively. This uptake showed a dose-dependent increase, the saturation point being reached at high concentrations of mannosyl residues/240 mM mannose. Merging of man/BSA-FITC and S100 labeling showed their partial, but, significant colocalization. Ultrastructural analysis of ST88-14 cells after incubation with HRP-colloidal gold, without or with subsequent chasing at 37C, showed an initial location on the cell surface and temperature- and time-dependent internalization of the probe. Our findings suggest an efficient mannosylated ligand uptake system through putative lectin(s) that may be operational in inflammatory and immune responses.

Inhibition of endogenous MHC class II‐restricted antigen presentation by tacrolimus (FK506) via FKBP51

The effect of tacrolimus (FK506) on down-regulation of IL-2 production by T cells is considered to be mainly responsible for its strong suppression of immunological events. In this study, we show that FK506 also has an affect on antigen presentation by antigen-presenting cells in vitro. FK506 was able to inhibit the presentation of endogenous MHC class II-restricted minor histocompatibility antigens in primary dendritic cells (DC) in vitro, but cyclosporine A (CsA) and rapamycin (RAP) were not. RNA interference (RNAi)-mediated reduction of endogenous FK506-binding protein (FKBP)51 expression resulted in a marked decrease in antigen presentation, suggesting that FKBP51 plays a role in endogenous MHC class II-restricted antigen presentation. Since our model used naturally expressed cytosolic antigens in primary DC, these effects might have been due to novel properties of the immunosuppressive drugs and may allow us to elucidate a new paradigm for the immunosuppressive mechanism of FK506.

Disruption of MHC Class II-Restricted Antigen Presentation by Vaccinia Virus

Vaccinia virus (VV), currently used in humans as a live vaccine for smallpox, can interfere with host immunity via several discrete mechanisms. In this study, the effect of VV on MHC class II-mediated Ag presentation was investigated. Following VV infection, the ability of professional and nonprofessional APC to present Ag and peptides to CD4+ T cells was impaired. Viral inhibition of class II Ag presentation could be detected within 1 h, with diminished T cell responses dependent upon the duration of APC infection and virus titer. Exposure of APC to replication-deficient virus also diminished class II Ag presentation. Virus infection of APC perturbed Ag presentation by newly synthesized and recycling class II molecules, with disruptions in both exogenous and cytoplasmic Ag presentation. Virus-driven expression of an endogenous Ag, failed to restore T cell responsiveness specific for this Ag in the context of MHC class II molecules. Yet, both class II protein steady-state and cell surface expression were not altered by VV. Biochemical and functional analysis revealed that VV infection directly interfered with ligand binding to class II molecules. Together, these observations suggest that disruption of MHC class II-mediated Ag presentation may be one of multiple strategies VV has evolved to escape host immune surveillance.

Clinical significance of MHC class II-associated invariant chain expression in human gastric carcinoma

MHC class II antigens serve as restricted elements for cell presenting antigens to CD4+ helper T cells. CD4+ T cells and CD8+ cytotoxic T cells, which are tumor-infiltrating lymphocytes (TILs), and play a major role in the survey and attack against tumor cells in primary lesions. Invariant chain (Ii) has several functions in MHC class II-restricted antigen presentation. In addition, Ii is found to be closely involved in the regulation of anti-tumor immunity in several tumor types. However, the significance of Ii expression in tumor cells is not fully illustrated. Immunohistochemical staining of Ii expression was performed in 58 cases of human gastric carcinoma specimens. The prognostic analysis of patients with gastric carcinoma was also performed. A total of 67.2% (39/58) gastric carcinomas were found to be Ii-positive, whereas only 20.7% (12/58) showed positive immunoreactivity with anti-MHC class II determinants. Furthermore, Ii expression showed significant correlation with the differentiation of gastric carcinoma (p<0.05). Ii expression also showed an inverse correlation with the frequency of TILs around carcinoma tissues, as well as with the prognosis of gastric carcinoma (p<0.01). Ii expression is closely correlated with anti-tumor immunity in human gastric carcinoma. Therefore, Ii may serve as an independent clinical marker for poor biological behavior and prognostic analysis in patients with gastric carcinoma.

FcγR-mediated uptake and processing of antigen–immunoglobulin complexes by professional antigen-presenting cells

Rheumatoid arthritis is characterized by the presence of autoantibodies. Various animal models for arthritis have shown a critical role for antibodies in the induction and progression of the disease, with complement and Fc receptors as the key effector mechanisms activated by antigen–antibody immune complexes (IC) in the effector phase of the disease. Although they are required for the perpetuation of the disease, the possible mechanisms by which Fc receptors could contribute to the chronic inflammation in arthritis are still unclear. It is known, however, that crosslinking FcγR on effector cells induces a variety of cellular responses, ranging from phagocytosis to secretion of inflammatory mediators and antibody-dependent cell cytotoxicity. Furthermore, FcγRs on dendritic cells (DC) are involved in the enhanced MHC class II-restricted presentation of antigen from IC to CD4+ T cells. Considering that also other antigen-presenting cells (APC) (like B cells and macrophages) express FcγR, this could be a possible mechanism of exacerbating/maintaining inflammation in arthritis. Therefore, we sought to explore the role of FcγR and complement in the MHC class II-restricted antigen presentation in vivo and to identify the APC involved in this process. To gain more insight into the ability of various types of APC to take up and present IC to T cells in vivo, we infused ovalbumin (OVA)-IC into naive mice. Direct ex vivo isolation of the different APC subsets showed that only CD11c+ cells, but not macrophages and B cells, are able to (cross-)present efficiently antigen from IC to T cells, although both macrophages and DC are able to capture IC efficiently. Furthermore, depletion of CD11c+ cells, using transgenic mice, abrogated the enhanced presentation of antigen in IC, confirming that DC are the predominant APC involved in (cross-)presentation of IC. To study the contribution of different FcγRs (FcγRI, FcγRII and FcγRIII) in IC-facilitated antigen presentation, we injected OVA-IC in wild-type mice and Fcγ R-knockout mice that have received 3 days earlier CFSE-labeled OVA-specific T cells. Our results indicate that activation of OVA-specific T cells in vivo is 10 times more efficient upon uptake of antibody-complexed OVA than soluble OVA. This effect was absent in mice lacking FcγRI, FcγRII and FcγRIII, but not in complement factor 3 knockout mice, indicating that the enhanced efficiency was FcγR mediated. Together, these results indicate that the enhanced presentation of antigen in IC and the subsequent activation of T cells in vivo is mediated primarily by DC, not by macrophages or B cells. Therefore, we consider it more likely that the IC-related contribution of macrophages to rheumatoid arthritis is associated with the release of proinflammatory cytokines and molecules upon activation induced by FcγR crosslinking, than to the enhanced activation of autoreactive CD4+ T cells. The ability to orchestrate and steer the T-cell responses is the responsibility of DC, further emphasizing the crucial role of DC in controlling (ongoing) T-cell responses.

Human cathepsin S, but not cathepsin L, degrades efficiently MHC class II-associated invariant chain in nonprofessional APCs.

MHC class II-restricted antigen presentation plays a central role in the immune response against exogenous antigens. The association of invariant (Ii) chain with MHC class II dimers is required for proper antigen presentation to CD4+ T cells by antigen-presenting cells. MHC class II complexes first traffic through the endocytic pathway to allow Ii chain degradation and antigenic peptide loading before their arrival at the cell surface. In recent years, a considerable effort has been directed toward the identification of proteases responsible for Ii chain degradation. Targeted gene deletion in mice has allowed a precise description of the cysteine proteases involved in the last step of Ii chain degradation. By using nonspecialized cellular models expressing MHC II molecules, we are now exploring the contribution of known cysteine proteases to human Ii chain processing. Surprisingly and contrary to the situation in mouse, cathepsin S was found to be the only human cysteine protease able to efficiently degrade the Ii-p10 fragment in epithelial cells. This selectivity has implications for thymic selection and indicates that differences between man and mice are probably more profound at this level than expected.