Adaptive Immune System


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2008-09-09-15_adaptive_immunityAdaptive Immunity, also called acquired immunity is the response of antigen specific lymphocytes to antigen. Host defenses are mediated by B and T cells following exposure to antigen, thus exhibiting specificity, diversity, memory and self/non self recognition. Adaptive immune responses are generated by clonal selection of lymphocytes. There is a lag time between exposure and maximal response and exposure leads to immunological memory.

In this section you will find explanations of the mechanisms and cells involved.

hyper-igm-syndromeThe following graphics depict how naïve B lymphocytes develop in the bone marrow and migrate to the secondary lymphoid organs where they are primed for antibody production. The cells then contact CD4+helper T lymphocytes, express CD154 and cytokines with the resulting differentiation of B lymphocytes into plasma cells.

When there is an error in this process we see a failure of CD40 stimulation by CD154.  This failure of CD40 stimulation prevents the B [simple_tooltip content=’A type of white blood cell that plays an important and integral role in the body’s defenses. There are two main classes of lymphocytes, namely B lymphocytes (humoral immunity) and T lymphocytes (cell – mediated immunity).’]lymphocyte[/simple_tooltip] from receiving the required activation signal to differentiate into a plasma cell which is then capable of secreting IgM or switching to a different antibody isotype such as IgG, IgA or IgE. The pathological condition is called hyper-IgM syndrome which is the failure of CD4+ helper T lymphocytes to express cell surface CD154 receptors.

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The cells of the adaptive immune system that specifically recognise antigenic peptides associated with HLA Class I receptors are CD8+ cytotoxic T lymphocytes via the T cell receptor (TCR), while the cells of the adaptive immune system that specifically recognise antigenic peptide associated with HLA Class II receptors are CD4+ helper T lymphocytes via the T cell receptor (TCR).

The T cell receptor is a cell surface receptor consisting of an alpha and a beta chain that along with the [simple_tooltip content=’Found on Cytotoxic T lymphocytes (CTL) and natural killer cells. The CD8 receptor on CTL binds to HLA class I and the interaction causes CD8 T cell activation. These cells are able to identify and kill cells infected primarily with viruses, but also many bacterial infections.’]CD8[/simple_tooltip] or [simple_tooltip content=’Is a receptor found on helper T cells and monocytes. The CD4 receptor on helper T cells binds to HLA class II and the interaction causes CD4 helper T cell activation. CD4+ T cells coordinate the immune response by releasing cytokines and signalling to other cells via cell-cell contact that enables others immune cells to perform their specialised functions (such as B cells). The number of CD4 cells in a sample of blood is an indicator of the health of the immune system. A normal CD4 count ranges from 500 to 1500. HIV infects and kills CD4 cells, leading to a weakened immune system and lower CD4 counts.
‘]CD4[/simple_tooltip] receptors, contacts the peptide antigen and the HLA class I or HLA class II receptor respectively. High diversity of TCR [simple_tooltip content=’In general, high affinity ligand binding results from greater intermolecular force between the ligand and its receptor.
Low affinity ligand binding involves less intermolecular force between the ligand and its receptor.

‘]binding affinity[/simple_tooltip] is achieved by genetic rearrangement of the TCR genes when new T lymphocytes develop.

In this section we explain the mechanisms of HLA class I and HLA class II in more detail with the aid of our unique graphics.

HLA Class I

hla-class-1The human leukocyte antigen (HLA) class I set of genes can be found on chromosome 6 and consists of 3 different alleles, designated HLA-A, HLA-B and HLA-C. Each allele encodes a membrane-bound alpha chain of the HLA class I cell surface receptor. The alpha chain associates non-covalently with a protein called beta 2-microglobulin which is not membrane-bound. The alpha-chain folds in a special way that creates a groove whereby small peptides of 9-12 amino acids long can fit snugly into the lining of the groove. The peptides are derived from proteins made in the cytosol of all cells other than red blood cells. This sampling mechanism allows proteins that are produced by intracellular pathogens such as viruses or certain types of bacteria as well as aberrant proteins produced by certain cancers to be detected by the immune system. There is a specific mechanism in place within the cell that processes cytosolic proteins and generates antigenic peptides that are associated with HLA class I receptors.

The cells of the adaptive immune system that specifically recognise antigenic peptides associated with HLA class I receptors are CD8+ cytotoxic T lymphocytes via the T cell receptor (TCR). The T cell receptor is a cell surface receptor consisting of an alpha and a beta chain that with the help of the [simple_tooltip content=’

Found on Cytotoxic T lymphocytes (CTL) and natural killer cells. The CD8 receptor on CTL binds to HLA class I and the interaction causes CD8 T cell activation. These cells are able to identify and kill cells infected primarily with viruses, but also many bacterial infections.

‘]CD8[/simple_tooltip] receptor contacts the peptide antigen and HLA class I receptor. High diversity of TCR[simple_tooltip content=’In general, high affinity ligand binding results from greater intermolecular force between the ligand and its receptor.
Low affinity ligand binding involves less intermolecular force between the ligand and its receptor.

‘] binding affinity[/simple_tooltip] is achieved by genetic rearrangements of the TCR genes when new T lymphocytes develop. Once activated, these CD8+ cytotoxic T lymphocytes have the ability to destroy infected cells displaying antigenic peptides associated with HLA class I receptors.  The killing mechanism involves the release of perforin and potent cell degrading molecules.

 To prevent autoimmune responses the regulation of CD8+ cytotoxic T lymphocytes is very strict. New CD8+ cytotoxic T lymphocytes that develop in the bone marrow are first directed to the thymus gland where they are not permitted to develop further if they have high affinity recognition responses to “self”-antigens that are displayed on HLA class I receptors expressed on thymic cells. T lymphocytes that do not respond leave the thymus and migrate to the T cell zone of lymph nodes for stimulation by antigen presenting cells such as dendritic cells. Dendritic cells are professional antigen presenting cells that transport antigens from sites of inflammation to the lymph nodes where they can present peptide antigens associated with HLA class I receptors to unstimulated CD8+ cytotoxic T lymphocytes. Newly generated CD8+ cytotoxic T lymphocytes that recognise peptide antigens presented by dendritic cells are primed to proliferate and differentiate into killing cells, however, before this can occur, an activation signal from an activated CD4+ helper T lymphocyte is needed. Following activation by a CD4+ helper T [simple_tooltip content=’

A type of white blood cell that plays an important and integral role in the body’s defenses. There are two main classes of lymphocytes, namely B lymphocytes (humoral immunity) and T lymphocytes (cell – mediated immunity).

‘]lymphocyte[/simple_tooltip], the CD8+ cytotoxic T lymphocyte proliferates by clonal expansion and produces effector cells. The effector cells migrate to sites of inflammation and are capable of killing infected cells bearing the same antigen associated with HLA class I receptors.  Memory CD8+ T lymphocytes are also generated to establish long-term immunity.

Click here to view the associated case study

Download a combined PDF with all the graphics

HLA Class II

hla-class-2The human leukocyte antigen ([simple_tooltip content=’HLA is Human Leukocyte Antigen which is part of the Major Histocompatibility Complex (MHC) which are a set of genes that, in part, direct T cell mediated immunity. There are two classes of MHC that are involved with directing T cell immunity: class I present peptides to CD8+ T cells and class II present peptides to CD4+ T cells. The peptides presented by either classes of MHC are derived from either “self” (own proteins) or from invading pathogens. HLA are one of the most polymorphic genes, meaning that many variants exist and the pairs of inherited genes create a unique set of immune responses in each person. HLA are known to be associated with different diseases and with transplantation compatibility/ incompatibility.

‘]HLA[/simple_tooltip]) class II set of genes maps to chromosome 6 and consists of 3 different loci designated HLA-DR, HLA-DP and HLA-DQ. Each locus encodes a membrane-bound alpha and beta chain of the HLA class II cell surface receptor. External domains of both the alpha and beta chains fold in such a way that they create a binding site for peptides of 12-25 amino acids long. The ends of the binding cleft are open and allow the peptide to extend outside the binding region. The peptides are derived from proteins sampled in the extracellular environment by antigen presenting cells. This mechanism allows proteins that are produced by extracellular pathogens such as bacteria to be detected by the immune system. The antigens are sampled by specialised antigen presenting cells such as dendritic cells and macrophages as well as B lymphocytes. Dendritic cells and macrophages take up the antigens by phagocytosis while B lymphocytes take up antigens by B-cell receptor mediated endocytosis. Following antigen uptake there is a specific mechanism in place within these cells that processes proteins and generates antigenic peptides that are bound to cell surface HLA class II receptors.

The cells of the adaptive immune system that specifically recognise antigenic peptide associated with HLA class II receptors are [simple_tooltip content=’

Is a receptor found on helper T cells and monocytes. The CD4 receptor on helper T cells binds to HLA class II and the interaction causes CD4 helper T cell activation. CD4+ T cells coordinate the immune response by releasing cytokines and signalling to other cells via cell-cell contact that enables others immune cells to perform their specialised functions (such as B cells). The number of CD4 cells in a sample of blood is an indicator of the health of the immune system. A normal CD4 count ranges from 500 to 1500. HIV infects and kills CD4 cells, leading to a weakened immune system and lower CD4 counts.

‘]CD4[/simple_tooltip]+ helper T lymphocytes via the T cell receptor (TCR). The T cell receptor is a cell surface receptor consisting of an alpha and a beta chain that along with the receptors contacts the peptide antigen and the HLA class II receptor. High diversity of TCR [simple_tooltip content=’

In general, high affinity ligand binding results from greater intermolecular force between the ligand and its receptor.
Low affinity ligand binding involves less intermolecular force between the ligand and its receptor.

‘]binding affinity[/simple_tooltip] is achieved by genetic rearrangement of the TCR genes when new T lymphocytes develop. Once activated, these cells migrate to sites of inflammation and stimulate the immune response by release of inflammatory cytokines. CD4+ helper T lymphocytes are also involved in activation of CD8+ cytotoxic T lymphocytes and B lymphocytes.

To prevent autoimmune responses the regulation of CD4+ helper T lymphocytes is very strict. New CD4+ helper T lymphocytes that develop in the bone marrow are first directed to the thymus gland where their development is terminated if they have high affinity recognition responses to “self”-antigens displayed on HLA class II receptors expressed on thymic cells. T lymphocytes that do not respond leave the thymus and migrate to the T cell zone of lymph nodes for stimulation by antigen presenting cells such as dendritic cells. Dendritic cells are professional antigen presenting cells that transport antigens from sites of inflammation to the lymph nodes. Here they can present peptide antigens associated with HLA class II receptors to unstimulated CD4+ helper T[simple_tooltip content=’A type of white blood cell that plays an important and integral role in the body’s defenses. There are two main classes of lymphocytes, namely B lymphocytes (humoral immunity) and T lymphocytes (cell – mediated immunity).’] lymphocytes[/simple_tooltip]. Newly generated CD4+ helper T lymphocytes that recognise peptide antigens presented by dendritic cells proliferate by clonal expansion and differentiate into effector cells that migrate to sites of inflammation and stimulate the immune response. Memory CD8+ T lymphocytes are also generated to establish long-term immunity.

Click here to view the associated case study

Download PDF with all graphics

 
 
 
 
 
 
International Union of Immunological SocietiesUniversity of South AfricaInstitute of Infectious Disease and Molecular MedicineScience Education PrizesElizabeth Glazer Pediatric Aids FoundationAlere