Immunoevasin

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Immunoevasins are proteins expressed by some viruses that enable the virus to evade immune recognition by interfering with MHC I complexes in the infected cell, therefore blocking the recognition of viral protein fragments by CD8+ cytotoxic T lymphocytes. Less frequently, MHC II antigen presentation and induced-self molecules may also be targeted. [1] [2] Some viral immunoevasins block peptide entry into the endoplasmic reticulum (ER) by targeting the TAP transporters. Immunoevasins are particularly abundant in viruses that are capable of establishing long-term infections of the host, such as herpesviruses. [1]

Contents

Mechanism

Each step in the peptide loading and presentation on MHC I (or MHC II) is a potential target for viral immunoevasins. These can range from targeting MHC I for lysosomal or cytoplasmic degradation, blocking TCR recognition of MHC I, inhibition of peptide transport into the ER or retention of MHC I in the ER or pre-Golgi. For MHC II, the possible evasion routes include MHC II-peptide assembly disruption, evading TCR recognition, MHC II degradation, and, conversely, CD4 co-receptor downregulation. [1] Prevention of NK cell activation may also be triggered by inhibition of presentation of induced-self molecules (ligands of NKG2D) or self molecules (MHC I) presentation (while also preventing the interaction with cytotoxic T lymphocytes). [3]

Examples

Herpes simplex virus (HSV-1 and HSV-2)

HSV produces a protein, ICP47, that binds to cytosolic surface of TAP, preventing peptides from ever entering the ER, which prevents the cascade reaction that leads to presenting the MHC complex on the cell surface. [4] [5]

Human cytomegalovirus (HCMV)

Conversely to the HSV-1, the ATP-binding of TAP is inhibited by HCMV US6 protein, indirectly resulting in decreased peptide transport to ER. [1] [5] [6] Retention of MHC I in the ER and possibly also inhibition of tapasin function may be attributed to US3 protein. [1] [5] [6] [7] [8] US2 and US11 proteins forward newly-synthesized MHC I to degradation in cytoplasm by dislocating the MHC I from the ER membrane into the cytosol. [1] [5] [6] [8] UL16 is able to bind induced-self molecules MICB, ULBP1 and ULBP2, ligands for NKG2D on NK cells. [9] Other immunoevasins, such as UL40, UL18, UL141, UL142 and pp65 also play a role in evading NK cell recognition. [6]

Murine cytomegalovirus (MCMV)

In MCMV infection, m152 protein is capable of withholding MHC I in ER-Golgi intermediate compartment (ERGIC). [1] [3] [8] [10] Together with the rest of m145 family, the proteins can also downregulate ligands of NKG2D, a group of induced-self receptors on NK cells. [2] [9] m06/gp48 protein binds to MHC I with the help of adaptor protein complex and directs it for lysosomal degradation from the secretory pathway. Another protein of MCMV, m04/gp34, can attach to MHC I in ER and, upon transport to the cell membrane, hinders the interaction of MHC I with TCR on cytotoxic T cells while inhibiting NK cell activation and cytotoxicity by exhibiting MHC I molecules on cell surface. [1] [3] [10] However, additional viral proteins may be required for successful transport of m04-bound MHC I to the cell membrane. [3]

Varicella zoster virus (VZV)

VZV protein ORF66 is, similarly to m152 protein in MCMV, responsible for MHC I retention in ERGIC. [5]

Kaposi's sarcoma-associated herpesvirus (KSHV)

KSHV proteins K3 and K5 increase the rate of endocytosis and subsequent degradation of MHC I from cell membrane. [1] [5] [7]

Human immunodeficiency virus (HIV)

Nef protein is capable of directly binding to cytosolic regions of MHC I and targeting them for degradation in lysosomes from trans-Golgi. [7] Nef and Vpu proteins can also direct CD4 co-receptor for lysosomal (Nef) or cytosolic proteasomal (Vpu) degradation, affecting the recognition of MHC II-bound peptides. [1]

Human herpesvirus 7 (HHV-7)

Protein U21 is responsible for targeting MHC I from the secretory pathway for lysosomal degradation. [1]

Epstein-Barr virus (EBV)

MHC II molecule (HLA-DR) acts as a co-receptor for the EBV entry into the cell upon binding the gp42 viral protein. Upon proteolytic cleavage and secretion of gp42, the protein can bind to MHC II, hindering the interaction with CD4+ T helper lymphocytes. [1] BNLF2a protein, which is present only in the replicative phase of the viral life cycle, functions as an inhibitor of TAP, blocking both peptide and ATP binding. [5]

Adenovirus 5

The inhibition of interaction between TAP and tapasin (needed for peptide loading on the MHC I), as well as retention of MHC I in the ER, is accomplished by adenoviral E19 protein. [1] [5]

Murine herpesvirus 68 (MHV-68)

The protein mK3 acts in a multitude of ways, including TAP complex destabilization and dislocation of MHC I to cytoplasm. [1] [5] [6]

Other

TAP function can also be inhibited by UL49.5 protein produced by bovine herpesvirus 1, pseudorabies virus, and equine herpesvirus 1. [1] [5]

Research and therapeutic significance

Thanks to the research on immunoevasins, several molecular mechanisms were clarified, such as MHC I processing mechanism, TAP-independent peptide presentation, MHC I peptide-loading complex (PLC)-independent antigen presentation pathways, cross-presentation and ER-associated degradation (ERAD). [5] In the future, the use or knockouts of immunoevasins (where mutated or deleted immunoevasin genes would not interfere with antigen presentation on MHC I complexes upon viral infection, resulting in recognition and targeting of infected cells by T cells) may be used for vaccine development for HCMV, gene therapy, transplantation and tumor-specific immunotherapy. [5] [8]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect the antigen presented on major histocompatibility complex (MHC) on infected cell surfaces, triggering cytokine release, causing the death of the infected cell by lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

Antigen processing, or the cytosolic pathway, is an immunological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage of antigen presentation pathways. This process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or intracellular pathogens, or from phagocytosed pathogens ; subsequent presentation of these antigens on class I or class II major histocompatibility complex (MHC) molecules is dependent on which pathway is used. Both MHC class I and II are required to bind antigens before they are stably expressed on a cell surface. MHC I antigen presentation typically involves the endogenous pathway of antigen processing, and MHC II antigen presentation involves the exogenous pathway of antigen processing. Cross-presentation involves parts of the exogenous and the endogenous pathways but ultimately involves the latter portion of the endogenous pathway.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.

<span class="mw-page-title-main">MHC class I</span> Protein of the immune system

MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on platelets, but not on red blood cells. Their function is to display peptide fragments of proteins from within the cell to cytotoxic T cells; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

<span class="mw-page-title-main">Antigen presentation</span> Vital immune process that is essential for T cell immune response triggering

Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, now bound to the major histocompatibility complex (MHC), is transported to the surface of the cell, a process known as presentation, where it can be recognized by a T-cell receptor. If there has been an infection with viruses or bacteria, the cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

<span class="mw-page-title-main">MHC class II</span> Protein of the immune system

MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses.

<span class="mw-page-title-main">HLA-A</span> Protein-coding gene in the species Homo sapiens

HLA-A is a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of human MHC class I transmembrane proteins. The others are HLA-B and HLA-C. The protein is a heterodimer, and is composed of a heavy α chain and smaller β chain. The α chain is encoded by a variant HLA-A gene, and the β chain (β2-microglobulin) is an invariant β2 microglobulin molecule. The β2 microglobulin protein is encoded by the B2M gene, which is located at chromosome 15q21.1 in humans.

<span class="mw-page-title-main">Minor histocompatibility antigen</span>

Minor histocompatibility antigen are peptides presented on the cellular surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides. These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules's antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities' proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.

Ly49 is a family of membrane C-type lectin-like receptors expressed mainly on NK cells but also on other immune cells. Their primary role is to bind MHC-I molecules to distinguish between self healthy cells and infected or altered cells. Ly49 family is coded by Klra gene cluster and include genes for both inhibitory and activating paired receptors, but most of them are inhibitory. Inhibitory Ly49 receptors play a role in the recognition of self cells and thus maintain self-tolerance and prevent autoimmunity by suppressing NK cell activation. On the other hand, activating receptors recognise ligands from cancer or viral infected cells and are used when cells lack or have abnormal expression of MHC-I molecules, which activate cytokine production and cytotoxic activity of NK and immune cells.

NKG2 also known as CD159 is a receptor for natural killer cells. There are 7 NKG2 types: A, B, C, D, E, F and H. NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes with CD94 to make an inhibitory receptor (CD94/NKG2).

<span class="mw-page-title-main">HLA-DM</span>

HLA-DM is an intracellular protein involved in the mechanism of antigen presentation on antigen presenting cells (APCs) of the immune system. It does this by assisting in peptide loading of major histocompatibility complex (MHC) class II membrane-bound proteins. HLA-DM is encoded by the genes HLA-DMA and HLA-DMB.

<span class="mw-page-title-main">ULBP2</span> Protein-coding gene in the species Homo sapiens

UL16 binding protein 2 (ULBP2) is a cell surface glycoprotein encoded by ULBP2 gene located on the chromosome 6. ULBP2 is related to MHC class I molecules, but its gene maps outside the MHC locus. The domain structure of ULBP2 differs significantly from those of conventional MHC class I molecules. It does not contain the α3 domain and the transmembrane segment. ULBP2 is thus composed of only the α1α2 domain which is linked to the cell membrane by the GPI anchor.

<span class="mw-page-title-main">ULBP1</span> Protein-coding gene in the species Homo sapiens

UL16 binding protein 1 (ULBP1) is a cell surface glycoprotein encoded by ULBP1 gene located on the chromosome 6. ULBP1 is related to MHC class I molecules, but its gene maps outside the MHC locus. The domain structure of ULBP1 differs significantly from those of conventional MHC class I molecules. It does not contain the α3 domain and the transmembrane segment. ULBP1 is thus composed of only the α1α2 domain which is linked to the cell membrane by the GPI anchor. It functions as a stress-induced ligand for NKG2D receptor. ULBP1 is, for example, upregulated during HCMV infection. Binding of HCMV-encoded UL16 glycoprotein to ULBP1 interferes with cell surface localization of ULBP1; this represents another mechanism by which HCMV-infected cells might escape the immune system.

<span class="mw-page-title-main">NKG2D</span> Protein-coding gene in the species Homo sapiens

NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.

Induced-self antigen is a marker of abnormal self, which can be recognized upon infected and transformed cells. Therefore, the recognition of "induced self" is an important strategy for surveillance of infection or tumor transformation - it results in elimination of the affected cells by activated NK cells or other immunological mechanisms. Similarly γδ T cells can recognize induced-self antigens expressed on cells under stress conditions.

CD94/NKG2 is a family of C-type lectin receptors which are expressed predominantly on the surface of NK cells and a subset of CD8+ T-lymphocyte. These receptors stimulate or inhibit cytotoxic activity of NK cells, therefore they are divided into activating and inhibitory receptors according to their function. CD94/NKG2 recognize nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse).

<span class="mw-page-title-main">Peptide loading complex</span>

The peptide-loading complex (PLC) is a short-lived, multisubunit membrane protein complex that is located in the endoplasmic reticulum (ER). It orchestrates peptide translocation and selection by major histocompatibility complex class I (MHC-I) molecules. Stable peptide-MHC I complexes are released to the cell surface to promote T-cell response against malignant or infected cells. In turn, T-cells recognize the activated peptides, which could be immunogenic or non-immunogenic.

References

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