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MHC molecules are not randomly distributed on the plasma membrane but instead are present in discrete nanoclusters. The mechanisms that control formation of MHC I nanoclusters and the importance of such structures are incompletely understood. Here, we report a molecular association between tetraspanin-5 (Tspan5) and MHC I molecules that started in the endoplasmic reticulum and was maintained on the plasma membrane. This association was observed both in mouse dendritic cells and in human cancer cell lines. Loss of Tspan5 reduced the size of MHC I clusters without affecting MHC I peptide loading, delivery of complexes to the plasma membrane, or overall surface MHC I levels. Functionally, CD8 T cell responses to antigen presented by Tspan5-deficient dendritic cells were impaired but were restored by antibody-induced reclustering of MHC I molecules. In contrast, Tspan5 did not associate with two other plasma membrane proteins, Flotillin1 and CD55, with or the endoplasmic reticulum proteins Tapasin and TAP. Thus, our findings identify a mechanism underlying the clustering of MHC I molecules that is important for optimal T cell responses. [ABSTRACT FROM AUTHOR]

Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy. [ABSTRACT FROM AUTHOR]

CD8 T cells recognize cancers when they detect antigenic peptides presented on a tumor's surface MHC-I molecules. Since MHC-I antigen presentation is not essential for cell growth or survival, many cancers inactivate this pathway, and thereby escape control by CD8 T cells. Such immune evasion allows cancers to progress and also become resistant to CD8 T- cell-based immunotherapies, such as checkpoint blockade. Here, we review recent findings about the various different mechanisms that cancers use to impair antigen presentation, the consequence of such changes, and, in some cases, the potential to reverse these defects. • Cancers often escape immune control by inactivating MHC-I antigen presentation. • Immune evasion can arise from lesions in multiple antigen presentation components. • Such lesions can occur at multiple levels (in structural genes, transcription,etc). • Loss of MHC-I presentation often leads to resistance to T-cell-based immunotherapy. • Some antigen presentation defects in cancers may be reversible. [ABSTRACT FROM AUTHOR]

Since the discovery of MHC molecules, it has taken 40 years to arrive at a coherent picture of how MHC class I and MHC class II molecules really work. This is a story of the proteases and MHC-like chaperones that support the MHC class I and II molecules in presenting peptides to the immune system. We now understand that the MHC system shapes both the repertoire of presented peptides and the subsequent T cell response, with important implications ranging from transplant rejection to tumor immunotherapies. Here we present an illustrated review of the ins and outs of MHC class I and MHC class II antigen presentation. [ABSTRACT FROM AUTHOR]

The β1i, β2i and β5i immunoproteasome subunits have an important role in defining the repertoire of MHC class I-restricted epitopes. However, the impact of combined deficiency of the three immunoproteasome subunits in the development of protective immunity to intracellular pathogens has not been investigated. Here, we demonstrate that immunoproteasomes play a key role in host resistance and genetic vaccination-induced protection against the human pathogen Trypanosoma cruzi (the causative agent of Chagas disease), immunity to which is dependent on CD8+ T cells and IFN-γ (the classical immunoproteasome inducer). We observed that infection with T. cruzi triggers the transcription of immunoproteasome genes, both in mice and humans. Importantly, genetically vaccinated or T. cruzi-infected β1i, β2i and β5i triple knockout (TKO) mice presented significantly lower frequencies and numbers of splenic CD8+ effector T cells (CD8+CD44highCD62Llow) specific for the previously characterized immunodominant (VNHRFTLV) H-2Kb-restricted T. cruzi epitope. Not only the quantity, but also the quality of parasite-specific CD8+ T cell responses was altered in TKO mice. Hence, the frequency of double-positive (IFN-γ+/TNF+) or single-positive (IFN-γ+) cells specific for the H-2Kb-restricted immunodominant as well as subdominant T. cruzi epitopes were higher in WT mice, whereas TNF single-positive cells prevailed among CD8+ T cells from TKO mice. Contrasting with their WT counterparts, TKO animals were also lethally susceptible to T. cruzi challenge, even after an otherwise protective vaccination with DNA and adenoviral vectors. We conclude that the immunoproteasome subunits are key determinants in host resistance to T. cruzi infection by influencing both the magnitude and quality of CD8+ T cell responses. [ABSTRACT FROM AUTHOR]

Cross-presentation is the process whereby bone-marrow-derived antigen-presenting cells acquire, process and present exogenous antigen as peptides bound to MHC class I molecules to CD8+ T cells. Professional antigen-presenting cells acquire cell-associated antigen predominantly in the form of protein, then process and present antigenic peptides on their surface MHC class I molecules via several mechanisms and efficiently cross-prime naïve CD8+ T cells in vivo. This pathway is of considerable interest because it has an important role in the immune surveillance of tissues for pathogens and cancers. [Copyright &y& Elsevier]

It was originally thought that a cell's major histocompatibility complex (MHC) class I molecules presented peptides derived exclusively from proteins synthesized by the cell itself. However, in some circumstances, antigens from the extracellular environment can be presented on MHC class I molecules and stimulate CD8+ T-cell immunity, a process termed cross-presentation. Cross-presentation was originally discovered as an obscure phenomenon in transplantation immunity. However, it is now clear that it is a major mechanism by which the immune system monitors tissues and phagocytes for the presence of foreign antigen. Cross-presentation is the only pathway by which the immune system can detect and respond to viral infections or mutations that exclusively occur in parenchymal cells rather than in bone marrow-derived antigen-presenting cells (APCs). Professional APCs, such as dendritic cells, are the principal cells endowed with the capacity to cross-present antigens. In this process, the APCs acquire proteins from other tissue cells through endocytic mechanisms, especially phagocytosis or macropinocytosis. The internalized antigen can then be processed through at least two different mechanisms. In one pathway, the antigen is transferred from the phagosome into the cytosol, where it is hydrolyzed by proteasomes into oligopeptides that are then transported by the transporter associated with antigen processing to MHC class I molecules in the endoplasmic reticulum or phagosomes. In a second pathway, the antigen is cleaved into peptides by endosomal proteases, particularly cathepsin S, and bound by class I molecules probably in the endocytic compartment itself. Depending on the nature of the antigen, one or both of these pathways can contribute to cross-presentation in vivo. The outcome of cross-presentation can be either tolerance or immunity. Which of these outcomes occurs is thought to depend on whether antigens are acquired by themselves alone, leading to tolerance, or with immunostimulatory signals, leading to immunity. One source of such signals is from dying cells that release immunostimulatory ‘danger’ signals that promote the generation of immunity to their cellular antigens. In addition to the critical role of cross-presentation in normal immune physiology, this pathway has considerable potential for being exploited for developing subunit vaccines that elicit both CD4+ and CD8+ T-cell immunity. [ABSTRACT FROM AUTHOR]

Cross-priming is essential for generating cytotoxic T lymphocytes to viral, tumor, and tissue antigens that are expressed exclusively in parenchymal cells. In this process, the antigen-bearing parenchymal cells must somehow transfer their antigens to bone mar- row-derived professional antigen-presenting cells. Although intact proteins, small peptides, or peptide-heat shock protein complexes can all be acquired and presented by antigen-presenting cells, the physiologically relevant form of antigen that is actually transferred from parenchymal cells and cross-presented in vivo is unknown and controversial. To address this issue we have investigated the ability of fibroblasts stably expressing chicken ovalbumin con- structs targeted to different subcellular compartments to crossprime cytotoxic T lymphocytes. Although these transfectants generated similar amounts of the immunogenic ovalbumin peptide, their cross-priming activity differed markedly. Instead, the cells cross-priming ability correlated with their steady-state levels of ovalbumin protein and/or the physical form/location of the protein. Moreover, in subcellular fractionation experiments, the cross- priming activity colocalized with antigenic protein. In addition, depletion of intact protein antigen from these cell fractions eliminated their cross-priming activity. In contrast the major heat shock protein candidates for cross-presentation were separable from the cell's main sources of cross-priming antigen. Therefore, cellular proteins, rather than peptides or heat shock protein! peptide complexes, are the major source of antigen that is transferred from antigen-bearing cells and cross-presented in vivo. [ABSTRACT FROM AUTHOR]

Originally published as 398, 77?80; 1999Cytotoxic T lymphocytes (CTLs) are thought to detect viral infections by monitoring the surface of all cells for the presence of viral peptides bound to major histocompatibility complex (MHC) class I molecules. In most cells, peptides presented by MHC class I molecules are derived exclusively from proteins synthesized by the antigen-bearing cells. Macrophages and dendritic cells also have an alternative MHC class I pathway that can present peptides derived from extracellular antigens; however, the physiological role of this process is unclear. Here we show that virally infected non-haematopoietic cells are unable to stimulate primary CTL-mediated immunity directly. Instead, bone-marrow-derived cells are required as antigen-presenting cells (APCs) to initiate anti-viral CTL responses. In these APCs, the alternative (exogenous) MHC class I pathway is the obligatory mechanism for the initiation of CTL responses to viruses that infect only non-haematopoietic cells. [ABSTRACT FROM AUTHOR]

For CD8 T lymphocytes to mount responses to cancer and virally‐infected cells, dendritic cells must capture antigens present in tissues and display them as peptides bound to MHC‐I molecules. This is most often accomplished through a pathway called antigen cross‐presentation (XPT). Here, we report that the vesicular trafficking protein Rab39a is needed for optimal cross‐presentation by dendritic cells in vitro and cross‐priming of CD8 T cells in vivo. Without Rab39a, MHC‐I presentation of intraphagosomal peptides is inhibited, indicating that Rab39a converts phagosomes into peptide‐loading compartments. In this process, Rab39a promotes the delivery of MHC‐I molecules from the endoplasmic reticulum (ER) to phagosomes, and increases the levels of peptide‐empty MHC‐I conformers that can be loaded with peptide in this compartment. Rab39a also increases the levels of Sec22b and NOX2, previously recognized to participate in cross‐presentation, on phagosomes, thereby filling in a missing link into how phagosomes mature into cross‐presenting vesicles. Synopsis: Antigen cross‐presentation is essential for CD8 effector T‐cells to identify and eliminate cells that synthesize abnormal proteins due to mutations or viral infection. The small GTPase Rab39a stabilises phagosomal antigens and peptide‐empty MHC‐I molecules and promotes peptide loading of the latter, thus enhancing cross‐presentation by dendritic cells. Rab39a depletion decreases levels of peptide‐receptive MHC‐I molecules in the phagosomes.Rab39a loss increases phagosomal degradation of antigen and MHC‐I molecules.Rab39a boosts the level of NOX2 and Sec22 on the phagosome, thereby enhancing ROS accumulation and phagosome alkalinisation.Rab39a promotes the generation of peptide‐loaded MHC‐I complexes in phagosomes. [ABSTRACT FROM AUTHOR]

The principal mechanism by which the immune system eliminates tumors and viral infections is the cytotoxic T lymphocyte (CTL) response. However, when cells in tissues become infected or undergo malignant transformation, they are unable by themselves to alert the immune system to initiate a CTL response. Instead, bone marrow-derived antigen-presenting cells (APCs) that are billeted in tissues must acquire antigens from the affected sites, transport them to lymph nodes and then present them to naive CD8 T cells as peptides bound to major histocompatibility complex (MHC) class I molecules. APCs that carry out this immune surveillance function are dendritic cells and possibly macrophages. For tissue-tropic viruses that do not infect APCs and for tumors of parenchymal cells, the APC must acquire and present the antigens that are synthesized by the infected or tumor cell, a process that has been called 'cross-presentation.'

• Dendritic cells internalize exogenous antigens for cross-presentation on MHC I. • MHC I cross-presentation allows immune surveillance of viral infection and cancers. • Dendritic cells utilize distinct and overlapping pathways for cross-presentation. • Phagosomes acquire cytosolic and ER-derived proteins for MHC-I loading of peptides. In order to get recognized by CD8 T cells, most cells present peptides from endogenously expressed self or foreign proteins on MHC class I molecules. However, specialized antigen-presenting cells, such as DCs and macrophages, can present exogenous antigen on MHC-I in a process called cross-presentation. This pathway plays key roles in antimicrobial and antitumor immunity, and also immune tolerance. Recent advances have broadened our understanding of the underlying mechanisms of cross-presentation. Here, we review some of these recent advances, including the distinct pathways that result in the cross-priming of CD8 T cells and the source of the class I molecules presenting exogenous peptides. [ABSTRACT FROM AUTHOR]

To arise and progress, cancers need to evade immune elimination. Consequently, progressing tumors are often MHC class I (MHC-I) low and express immune inhibitory molecules, such as PD-L1, which allows them to avoid the main antitumor host defense, CD8+ T cells. The molecular mechanisms that led to these alterations were incompletely understood. In this study, we identify loss of the transcription factor IRF2 as a frequent underlying mechanism that leads to a tumor immune evasion phenotype in both humans and mice. We identified IRF2 in a CRISPR-based forward genetic screen for genes that controlled MHC-I Ag presentation in HeLa cells. We then found that many primary human cancers, including lung, colon, breast, prostate, and others, frequently downregulated IRF2. Although IRF2 is generally known as a transcriptional repressor, we found that it was a transcriptional activator of many key components of the MHC-I pathway, including immunoproteasomes, TAP, and ERAP1, whose transcriptional control was previously poorly understood. Upon loss of IRF2, cytosol-to-endoplasmic reticulum peptide transport and N-terminal peptide trimming become rate limiting for Ag presentation. In addition, we found that IRF2 is a repressor of PD-L1. Thus, by downregulating a single nonessential gene, tumors become harder to see (reduced Ag presentation), more inhibitory (increased checkpoint inhibitor), and less susceptible to being killed by CD8+ T cells. Importantly, we found that the loss of Ag presentation caused by IRF2 downregulation could be reversed by IFN-stimulated induction of the transcription factor IRF1. The implication of these findings for tumor progression and immunotherapy are discussed. [ABSTRACT FROM AUTHOR]