Full Answer
What is antigen presentation?
Antigen presentation is mediated by MHC class I molecules, and the class II molecules found on the surface of antigen-presenting cells (APCs) and certain other cells.
What is the exogenous pathway for antigen processing?
Exogenous pathway for antigen processing Endogenous pathway for antigen processing T cells or T lymphocytes can only recognize antigen when it is presented on the antigen-presenting cells along with the other cell surface component – MHC molecule (Major Histocompatibility Complex molecule).
What are endogenous antigens and how do they work?
They carry antigens, markers that alert the body to an infection and the need for an attack. Endogenous antigens are signals produced within your body's own cells (having been infected by a virus) that start an immune response. They alert cytotoxic T cells that a body cell is either infected with a virus, such as influenza, or has become cancerous.
What are the different pathways for antigen process and presentation?
So, to process and present both these types of antigens, we have two different pathways for antigen process and presentation known as exogenous and endogenous pathways. We will see both these pathways in good detail.
How do antigen-presenting cells process antigens?
Antigen-presenting cells (APC) are cells that can process a protein antigen, break it into peptides, and present it in conjunction with class II MHC molecules on the cell surface where it may interact with appropriate T cell receptors.
What is endogenous antigen presentation?
Antigens generated endogenously within these cells are bound to MHC-I molecules and presented on the cell surface. This antigen presentation pathway enables the immune system to detect transformed or infected cells displaying peptides from modified-self (mutated) or foreign proteins.
How are exogenous antigens processed?
Exogenous antigens are processed through the endoplasmic reticulum-associated degradation (ERAD) in cross-presentation by dendritic cells. Int Immunol.
How does antigen processing occur?
The usual process of antigen presentation through the MHC I molecule is based on an interaction between the T-cell receptor and a peptide bound to the MHC class I molecule. There is also an interaction between the CD8+ molecule on the surface of the T cell and non-peptide binding regions on the MHC class I molecule.
What are endogenous antigens?
Endogenous antigens are antigens found within the cytosol of human cells such as viral proteins, proteins from intracellular bacteria, and tumor antigens. Exogenous antigens are antigens that enter from outside the body, such as bacteria, fungi, protozoa, and free viruses.
How are exogenous antigens processed and presented?
Exogenous proteins, however, are primarily presented by MHC-II molecules. Antigens are internalized by several pathways, including phagocytosis, macropinocytosis, and endocytosis, and eventually traffic to a mature or late endosomal compartment where they are processed and loaded onto MHC-II molecules.
What is the difference between processing of endogenous antigens and that of exogenous antigens?
The key difference between endogenous and exogenous antigens is that the endogenous antigens generate within the cells while the exogenous antigens come from the outside of the body. Hence, endogenous antigens are intracellular while exogenous antigens are extracellular.
Is MHC 2 endogenous or exogenous?
MHC class II molecules present both extracellular (exogenous) and internally synthesized (endogenous) antigens to the CD4 T cells subset of lymphocytes. The mechanisms of endogenous antigen presentation are the subject of this review.
What is an exogenous pathway?
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What is endogenous pathway of antigen processing and presentation?
The endogenous pathway is used to present cellular peptide fragments on the cell surface on MHC class I molecules. If a virus had infected the cell, viral peptides would also be presented, allowing the immune system to recognize and kill the infected cell.
What is the difference between endogenous and exogenous pathway?
Exogenous antigens refer to the antigens that enter the body of the organism from the outside while endogenous antigens refer to the antigens produced from within the cell as a part of normal cell metabolism or when the cell is infected by bacteria or viruses.
What is an example of an exogenous antigen?
Exogenous antigens include particles considered foreign within the organism. For example, allergens (such as pollen), proteins from transplanted tissues and organs, and parts of microorganisms (such as coat, capsule, cell wall, flagella, fimbria, or toxin of bacteria, viruses, etc.)
What is the difference between processing of endogenous antigens and that of exogenous antigens?
The key difference between endogenous and exogenous antigens is that the endogenous antigens generate within the cells while the exogenous antigens come from the outside of the body. Hence, endogenous antigens are intracellular while exogenous antigens are extracellular.
Where does most exogenous antigen presentation?
Where does most exogenous antigen presentation take place? Most exogenous antigen presentation to T cells occurs in lymphoid tissues and organs located throughout the body, to which it is transported by dendritic cells.
What is the process of presenting endosomal peptides?
Some of the MHC class I molecules can be recycled and present endosomal peptides as a part of a process which is called cross-presentation. The usual process of antigen presentation through the MHC I molecule is based on an interaction between the T-cell receptor and a peptide bound to the MHC class I molecule.
What are the key elements of adaptive immunity?
In order to be capable of engaging the key elements of adaptive immunity (specificity, memory, diversity, self/nonself discrimination ), antigens have to be processed and presented to immune cells. Antigen presentation is mediated by MHC class I molecules, and the class II molecules found on the surface of antigen-presenting cells (APCs) ...
What are the genes that encode MHC class I?
Human MHC class I molecules are encoded by a series of genes – HLA-A, HLA-B and HLA-C (HLA stands for ‘Human Leukocyte Antigen’ , which is the human equivalent of MHC molecules found in most vertebrates). These genes are highly polymorphic, which means that each individual has his/her own HLA allele set. The consequences of these polymorphisms are differential susceptibilities to infection and autoimmune diseases that may result from the high diversity of peptides that can bind to MHC class I in different individuals. Also, MHC class I polymorphisms make it virtually impossible to have a perfect tissue match between donor and recipient, and thus are responsible for graft rejection.
How are peptides derived from ER?
Prior to entering the ER, peptides are derived from the degradation of proteins, which can be of viral- or self origin. Degradation of proteins is mediated by cytosolic- and nuclear proteasomes, and the resulting peptides are translocated into the ER by means of TAP.
What amino acids are translocated in a tap?
TAP translocates peptides of 8 –16 amino acids and they may require additional trimming in the ER before binding to MHC class I molecules. This is possibly due to the presence of ER aminopeptidase (ERAAP) associated with antigen processing.
What is an antigen?
An antigen is a foreign or “non-self” macromolecule that reacts with cells of the immune system. Not all antigens will provoke a response. For instance, individuals produce innumerable “self” antigens and are constantly exposed to harmless foreign antigens, such as food proteins, pollen, or dust components. The suppression of immune responses ...
Where are antigens transported?
Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. Dendritic cells are immune cells that process antigen material; they are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the ...
What is the innate immune system?
The innate immune system contains cells that detect potentially harmful antigens, and then inform the adaptive immune response about the presence of these antigens. An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will ...
What is the role of cytotoxic T cells in the immune system?
Cytotoxic T cells destroy virus-infected cells in the cell-mediated immune response, and helper T cells play a part in activating both the antibody and the cell-mediated immune responses. Suppressor T cells deactivate T cells and B cells when needed, and thus prevent the immune response from becoming too intense.
What is the function of a macrophage?
Macrophages also function as APCs. Before activation and differentiation, B cells can also function as APCs. After phagocytosis by APCs, the phagocytic vesicle fuses with an intracellular lysosome forming phagolysosome. Within the phagolysosome, the components are broken down into fragments; the fragments are then loaded onto MHC class I ...
What are the three types of T cells?
There are three types of T cells: cytotoxic, helper, and suppressor T cells.
Can T lymphocytes respond to antigens?
Note that T lymphocytes cannot properly respond to the antigen unless it is processed and embedded in an MHC II molecule. APCs express MHC on their surfaces, and when combined with a foreign antigen, these complexes signal a “non-self” invader. Once the fragment of antigen is embedded in the MHC II molecule, the immune cell can respond.
What is the pathway of endogenous antigen processing and presentation over MHC-II molecules?
Alternative pathway of endogenous antigen processing and presentation over MHC-II molecules exists in medullary thymic epithelial cells (mTEC) via the process of autophagy. It is important for the process of central tolerance of T cells in particular the negative selection of autoreactive clones. Random gene expression of the whole genome is achieved via the action of AIRE and a self-digestion of the expressed molecules presented on both MHC-I and MHC-II molecules.
Which enzymes are involved in the antigen presentation pathway?
There are three compartments involved in this antigen presentation pathway: early endosomes, late endosomes or endolysosomes and lysosomes, where antigens are hydrolized by lysosome-associated enzymes (acid-dependent hydrolases, glycosidases, proteases, lipases). This process is favored by gradual reduction of the pH.
What is the presentation of native intact antigens to B cells?
Presentation of native intact antigens to B cells. B-cell receptors on the surface of B cells bind to intact native and undigested antigens of a structural nature , rather than to a linear sequence of a peptide which has been digested into small fragments and presented by MHC molecules. Large complexes of intact antigen are presented in lymph nodes ...
Why do T cells recognize only fragmented antigens displayed on cell surfaces?
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.
What are cytotoxic T cells?
Cytotoxic T cells (also known as T c, killer T cell, or cytotoxic T-lymphocyte (CTL)) express CD8 co-receptors and are a population of T cells that are specialized for inducing programmed cell death of other cells. Cytotoxic T cells regularly patrol all body cells to maintain the organismal homeostasis. Whenever they encounter signs of disease, caused for example by the presence of viruses or intracellular bacteria or a transformed tumor cell, they initiate processes to destroy the potentially harmful cell. All nucleated cells in the body (along with platelets) display class I major histocompatibility complex (MHC-I molecules). Antigens generated endogenously within these cells are bound to MHC-I molecules and presented on the cell surface. This antigen presentation pathway enables the immune system to detect transformed or infected cells displaying peptides from modified-self (mutated) or foreign proteins.
How are peptides transported to the endoplasmic reticulum?
Then, peptides are distributed to the endoplasmic reticulum (ER) via the action of heat shock proteins and the transporter associated with antigen processing (TAP) which translocates the cytosolic peptides into the ER lumen in an ATP-dependent transport mechanism. There are several ER chaperones involved in MHC-I assembly, such as calnexin, calreticulin and tapasin. Peptides are loaded to MHC-I peptide binding groove between two alpha helices at the bottom of the α1 and α2 domains of the MHC class I molecule. After releasing from tapasin, peptide-MHC-I complexes (pMHC-I) exit the ER and are transported to the cell surface by exocytic vesicles.
How do APCs migrate?
APCs undergo a process of maturation while migrating, via chemotactic signals, to lymphoid tissues, in which they lose the phagocytic capacity and develop an increased ability to communicate with T-cells by antigen-presentation. As well as in CD8+ cytotoxic T cells, APCs need pMHC-II and additional costimulatory signals to fully activate naive T helper cells.
Where are antigens concentrated in B cells?
Studies in vivo using two-photon microscopy to observe where and how B cells acquire particulate antigens, have shown that internalized antigens are frequently concentrated at the uropod of B cells that are migrating to the T cell zone 6. This suggests that following antigen acquisition, B cells continue to show a polarized phenotype. Furthermore, recent studies have shown that this asymmetric distribution of antigens within B cells is maintained throughout cell division, which leads to asymmetric antigen segregation among daughter cells; this, consequently, provides the daughter cells with differential capacities for antigen presentation 87. The daughter cells that have inherited larger amounts of antigens are more effective at stimulating cognate T cells, which might give them an advantage in competing for the limited T cell help that is available. Whether the generation of these unequal populations ultimately changes the effector fates of B cells in vivo remains to be elucidated.
Which cells can encounter soluble or large particulate antigens that are attached to the surface of neighbouring cells?
B cells can encounter soluble or large particulate antigens that are attached to the surface of neighbouring cells, such as macrophages, follicular dendritic cells (FDCs) or dendritic cells (DCs) 6, 7, 8, 9.
How does BCR internalize antigens?
BCR internalization and signalling. Antigens that are acquired by the BCR in either a soluble or a tethered form induce receptor endocytosis and signalling events, which are both equally important for B cells to become fully activated. The local secretion of hydrolases at the immunological synapse promotes the extraction of membrane-bound antigens 38, which suggests that antigen degradation occurs, at least partially, in the extracellular space and probably at the same time as the main intracellular pathway. Indeed, BCR engagement induces the maturation of late endosomal and lysosomal compartments, into which receptors are rapidly internalized and antigens are degraded 60 and processed to form MHC class II–peptide complexes ( Fig. 3 ). BCR internalization is clathrin-dependent 61 and relies on the ubiquitylation of the immunoglobulin α-chain 62 and the immunoglobulin heavy chain 63 of the BCR complex. Ubiquitylation of antigen–BCR complexes was recently shown to occur downstream of SYK-dependent signalling 64, which highlights that endocytic trafficking and signalling of the BCR are tightly linked. These events are also influenced by the nature of the antigen that binds to the BCR. Indeed, oligomeric antigens, such as those that are membrane-bound, were shown to trigger stronger BCR-mediated signalling and to promote more efficient endocytic trafficking of BCR–antigen complexes than monovalent antigens 65. Interestingly, BCR signalling continues within endocytic compartments, where it leads to the sequential phosphorylation of kinases that control the transcription of genes required for B cell activation 66.
What determines the size of the peptide antigen that will be presented to T cells?
The nature and amount of proteases that are secreted at the B cell synapse — an environment that is different from that of the lysosomal compartments — could also determine the size of the peptide antigen that will be presented to T cells. In addition, antigenic peptides that are generated in the extracellular space might also be directly loaded on cell surface MHC class II molecules, independently of the intracellular compartments. Indeed H2-DM, which is the chaperone that catalyses peptide loading on MHC class II molecules, has also been detected on the cell surface of both B cells and immature DCs 56, 57, where extracellular antigen processing and peptide loading was shown to take place. Interestingly, and similarly to DCs, B cells contain much lower levels of lysosomal proteases than macrophages 58. This favours the presentation of antigenic peptides on MHC class II molecules by limiting the complete destruction of the peptide determinants 59.
How do B cells differentiate into memory cells?
The selection of high-affinity B cell clones in the germinal centres is thought to be dependent on signals generated either by BCR crosslinking with antigens that are tethered to the surface of FDCs or by germinal centre T helper cells that have been stimulated by high-affinity B cell clones presenting uptaken antigen on MHC class II molecules 89. Recent studies using intravital microscopy imaging combined with in situ photoactivation to label germinal centre B cells have provided strong evidence that T helper cells in the germinal centre are the limiting factor in affinity-based selection 90.
Why is the severing of the cortical actin cytoskeleton necessary?
It has been suggested that the severing of the cortical actin cytoskeleton might be required to remove the barriers that restrict receptor diffusion 32, thus promoting BCR microcluster formation. Such a mechanism could be coupled to the inactivation of ERM proteins — driven by BCR stimulation — which also leads to a transient increase in BCR mobility and is required for efficient microcluster formation, for membrane spreading and to gather antigens at the synapse 26. In addition, the proteins that regulate actin cytoskeleton dynamics are essential to promote the development and the activation of B cells.
What is the role of the actin-dependent membrane in the formation of an immunological synapse?
The formation of an immunological synapse is associated with a rapid actin-dependent membrane spreading response at the antigen contact site, which increases the amount of BCR–antigen encounters and is required for the formation of signalling microclusters that contain recruited antigens and signalling molecules. This is followed by a contraction phase that is mediated by both the actin and microtubule cytoskeleton, in which antigen-containing microclusters are concentrated at the centre of the synapse by the microtubule motor dynein.
