Adaptive Immunity

1. Antigen Presentation
2. MHC Class 1 - Intracellular Microbes
3. MHC Class 2 - Extracellular Microbes
4. Primary and Secondary Immune Antibody-based Response
5. Quiz

• Antigen-presenting cells activate different T-lymphocytes, and T-lymphocytes help B-lymphocytes, to fight against invaders
• MHC is a series of proteins that the adaptive/acquired immune response needs to recognise foreign material
• Naïve T-cells (T-cells that have not yet met their antigen) differentiate into cytotoxic T-cells and several T-helper cells (Th1, Th2, Th17) which have different responses depending on the current active infection

To understand this article, we advise that you read the Innate Immune Response, or have a rough understanding of it.

As outlined in the previous article, the innate response is rapid, but it lacks memory and cannot change the strength of its response. The adaptive immune system fills this gap. So why does the adaptive immune response not start immediately fighting bacteria on infection?

While the innate immune response is coordinating the early ‘front line’ response against the invaders, the adaptive response must wait for its cells to become activated. Certain types of cells, called antigen presenting cells (APCs), are found throughout the body where they sample their environment for foreign antigens. APCs are a diverse group including macrophages, monocytes (white blood cells that circulate in the blood and mature into macrophages in the tissues), dendritic cells (cells in tissues such as the skin that present antigens to T-lymphocytes), Langerhans cells (dendritic cells of the skin), and B-lymphocytes.

Antigen Presentation

An antigen presenting cell, e.g. a macrophage, will phagocytose a foreign pathogen, as part of the innate immune response. After taking in the pathogen and degrading it within lysosomes, a small sample of the antigen from the pathogen is then displayed on the surface of the macrophage using a molecule called a Major Histocompatibility Complex (MHC). This display is called "presenting" the antigen (hence the name antigen presenting cell). This process can be broken down into 3 simple steps of: Capture (phagocytosis), Processing (digestion down to antigen fragments) and Presentation (using an MHC). 

The next step is T cell activation. This occurs when the T cell receptor of a T-lymphocyte binds the antigen-displaying MHC on the surface of the macrophage (or of another antigen presenting cell: dendritic cells are especially good at activating naïve T-cells). The need for the T cell receptor to recognise the specific antigen is what delays activation of the adaptive immune response. Once activated, helper T-lymphocytes help B-cells to produce specific antibodies. They signal to the B-cells using cytokines (chemical messenger proteins released by immune cells). T lymphocytes also begin to multiply and to mount their own attack against the invading pathogen. We’ll come back to T- and B-lymphocytes, as we need to discuss how the APCs do their job.

MHC class I and class II are the two main groups of cell-surface molecules that present antigenic peptides to T cells. In humans they are called human leucocyte antigens (HLA). The MHC class III region of the genome (our genetic code) encodes other immune proteins, including complement components (blood proteins that help to destroy microbes) and inflammatory mediators (chemical signals that drive inflammation); it is not a third class of peptide-presenting surface molecules.

There are two main classes:

MHC class I molecules, including HLA-A, HLA-B and HLA-C, are expressed on almost all nucleated cells. They usually present peptides from proteins made within the cell, including normal self proteins and proteins from intracellular pathogens (microbes that live inside our cells), to CD8 T cells (CD stands for “cluster of differentiation”, a numbered marker on the surface of T cells). The T-cell receptor recognises the peptide–MHC complex and CD8 acts as a co-receptor (a second surface molecule that helps the T cell grip the MHC molecule). Specialised antigen-presenting cells can also cross-present extracellular antigens (antigens from outside the cell) on class I, which is explained further below.

MHC class II molecules are characteristically expressed by professional antigen-presenting cells (cells whose main job is to present antigens to T cells), including dendritic cells, macrophages and B cells. Other cells, including epithelial cells (cells that line surfaces), can also carry class II molecules, and inflammation can switch this on. In the conventional pathway, antigen taken up from outside the cell is processed into peptides and presented to CD4 T cells. Uptake may involve phagocytosis or other forms of endocytosis; phagocytosis is not confined to professional antigen-presenting cells. The T-cell receptor recognises peptide–MHC II and CD4 acts as a co-receptor. Co-stimulatory signals (extra activating signals that the T cell needs as well as antigen recognition) and cytokines help determine T-cell activation and subsequent differentiation.

Key facts about MHCs (they matter in medicine because they affect infections, transplants and autoimmune disease):

• The MHC molecules have a broad specificity so that a single cell can present multiple antigens from the same microbe to increase the immune response.
• The specific HLA molecules on a person's MHCs affect how well the body deals with certain infections, e.g. HIV. Some people with HIV carry HLA molecules (such as HLA-B57 and HLA-B27) that are linked to good control of the virus and slow disease progression, because their T-cell response is effective. These HLA molecules present key viral peptides, which the virus needs in order to survive and cannot easily mutate. People whose HLA molecules only present non-crucial peptides (which the virus can mutate freely) are less likely to have this protection.
• A mismatch in MHC molecules between a donor and recipient in an organ transplant can cause rejection of the organ. If the organ transplanted is bone marrow, a mismatch in MHC molecules can result in graft versus host disease (GvHD). In GvHD, the new white blood cells produced by the donor marrow attack the host’s tissues.
• Having certain MHC molecules can predispose individuals to certain autoimmune conditions e.g. type 1 diabetes (the immune system destroys the insulin-making beta cells of the pancreas). HLA-DR3 and HLA-DR4 are the main high-risk types.

A helpful way of remembering which class of MHC binds to which CD receptor is:

When you multiply the MHC class and CD number together you should get 8:

MHC Class I binds to CD8+ (1x8)

MHC Class II binds to CD4+ (2x4)

Fighting off intracellular microbes - MHC Class 1

An intracellular organism, for example a virus invading a cell to take over its replication machinery, can infect any nucleated cell. For this reason, MHC class I is found on almost all nucleated cells.

An APC can present antigens on both MHC class I and MHC class II molecules. Cross-presentation specifically refers to the ability of some APCs to present extracellular (phagocytosed) antigens on MHC class I, allowing activation of CD8+ T cells.

So, if an APC (e.g. a macrophage) with its epitope bound to an MHC molecule arrives at a naïve T-cell, what happens next? (An epitope is the part of an antigen that the immune system recognises. An antibody attaches to it directly, whereas a T-cell recognises a short peptide fragment of it displayed on an MHC molecule.)

If the epitope is displayed on an MHC class I molecule, a T cell with the CD8+ receptor binds it and becomes an activated cytotoxic T-cell. This ‘killer’ cell then kills infected body cells that display the same antigen on MHC class I. 

Preview the Adaptive Immunity quiz