The two major components of the adaptive immune system are known as cellular and humoral immunity. For an effective immune system these two branches of the adaptive immune system must interact. The main effector cells of these two systems are the T and B-lymphocytes.

T and B-lymphocytes both develop from a common progenitor in the bone marrow. T cells then move on to fully develop in the thymus and B cells develop in the bone marrow (in the foetus they develop in the liver). Any T or B cells that are at rest are morphologically indistinguishable.

Features of T and B Cells

Both T and C cells are able to recognise and bind an antigen and show a specific memory. B cells recognise antigens with the surface membrane Ig – which determines the specificity of the cell. T cells recognise the antigen with the T cell receptor which has both variable and hypervariable regions similar to yet still distinct from those of the immunoglobulin molecules.

Stimulation of a T cell by a specific antigen leads to the generation of effector T cells, which may directly and specifically kill cells bearing the appropriate antigen (or have other protective effects)

T and B cells can be distinguished by; their surface cells markers or their antigens. Many of these have a functional role e.g. CD8 are T Cytotoxic cells.

Lymphocyte Cell Surface Markers

The role of the cell depends on the surface marker displayed. These are usually denoted as part of a ‘CD’ (Cellular determinate) system. Some of the most important surface markers are surface Ig and those cells that are CD4/8 positive. A cell that expresses CD8 on its surface has the role of a T-cytotoxic cell. A cell that is CD4 positive has the role of a T helper cell.

Development of T Cells

T-Cell initial develop in the bone marrow from the same precursor cell as B-cells. They then move to develop in the thymus. Within lobules of the thymus, these thymocytes (t-cells) as they are known, begin to develop as they cross from the thymic cortex to the medulla. It is at this point when rapid T cell receptor diversity occurs. There are two selection processes involved in the development of T cells:

• Active cells check the MHC (major histocompatability complex) displayed on the under-developed T-Cells (positive selection). If the MHC component is recognised, the cells move on towards the medulla. If not the cells die by apoptosis.
• The second type of selection (negative selection) is where any thymocytes that have antigenic specificity for self-antigens are destroyed by apoptosis.
• The remaining thymocytes go on to become fully mature T-cells, expressing T-cell receptors. However these two processes eliminate 95% of the under-developed T-cells.
• Cytokine receptors
  • This are for interaction with regulatory cytokines
  • Antibody receptors
    • These are specifically receptors for the Fc portion of IgG (FcR)
    • Complement Receptors
      • Phagocytic cells have receptors for C3 – mainly C3b subcomponents (opsonisation of antigens)
      • Adherence Molecules
        • The molecules are important in the movement and adhesion of lymphocytes in and between tissues. Integrins are adhesion molecules found on resting T cells that bind with receptors of circulatory vessel walls. Correspondingly, T-cells have selectin receptors that bind to selectin on the circulatory walls.
        • Major Histocompatibility Complex (MHC) Antigens
          • These are cell surface molecules that are highly polymorphic and highly important in immune cell communications.
          • Transplant and Immunogenetics
            • Transplant rejection is usually always the result of a difference in the MHC of the donor and the recipient.

Other Molecules on Lymphocyte Surfaces

• Graft Rejection and MHC – Types of Grafts
  • Autografts – Between two sites of the same animal
  • Isograft – Between genetically identical individuals
  • Allograft – Between genetically different individuals of the same species
  • Xenograft – Between different species

Graft rejection results from the recognition of differences between graft and host. The cell surface antigens which are recognised are foreign are the MHC antigens.

Types of Histocompatibility Complexes

• Class I
  • These are found on all nucleated mammalian cells (Not red blood cells)
  • Class II
    • Expressed on the surface of immunological cells
    • They are expressed on dendritic cells and are inducible on macrophages, T lymphocytes and B-lymphocytes.
    • Some diseases cause expression of Class II MHC on epithelial or endothelial cells

Variability of MHC

Due to the high polymorphism encoded by MHC genes each individual has an almost unique set of histocompatibility antigens hence why it is often difficult ensure tissue grafts are not rejected. Sometime referred to as leukocyte antigens (LA) the MHC system can be found in the dog (DLA), horse (ELA), sheep (OLA), cat (FLA), pig (SLA), goat (GLA and man (HLA).

The class I genes found on all mammalian nucleated cells are encoded by the regions A, B and C of a loci concerning MHC expression. There is also a region D which codes for class II molecules.

As each individual chromosome has a pair, (one inherited from each parent), each individual will therefore express 2 sets of MHC antigen.

Transplant rejection therefore occurs because the host recognises donor MHC class I as a foreign antigen. This ‘foreign antigen’ is then attacked by cytotoxic (CD8) T-cells. This happens because the cytotoxic cell recognises the foreign class I molecule with its T-cell receptor in association with its CD8 molecule.

Antigen Presenting Cells

B-cells are able to directly bind soluble antigens, due to their high affinity for them; on the other hand T cells (which have a low binding affinity) are specialised to recognise antigens on the surface of other cells. These antigen presenting cells (APC) are required to take up and process antigen. They then present it to T cells before they can respond. APC have large amounts of MHC class II on their surface which is essential in the process of effective presentation of the exogenous antigen to the T-helper cells.

Exogenous antigens enter the body and are bound and internalised by the APC, this process normally occurs in secondary lymphoid tissue. The antigen is then degraded by the action of enzymes in phagolysosomes and the broken down, smaller peptides which result are moved to the cell surface and expressed in association with MHC class II. It is this association which is then recognised by antigen specific T-Helper cells.

Dendritic cells (immune cells) are the most potent APC and have the highest levels of surface MHC Class II. Dendritic cells do not appear to degrade antigens internally such as phagocytes, but either digest the antigen externally (extracellularly) or they acquire the peptides they intend to express from the degradation performed by other cells. Macrophages only express class II when they are activated.

Activated B cells can also act as APC. The membrane Ig units bind the antigen and process and present in association with MHC class II in a similar fashion as before to the T-helper cells. Presenting by this system requires fewer antigens than the presentation by dendritic cells. However it cannot produce IL-1 (interleukine-1) which is a cytokine that activates T-cells.

Cytokines

• Cytokines are soluble products which are released from any cell.
• Interleukins are soluble products released from leukocytes.
• Monokines are soluble products released specifically from monocytes
• Lymphokines are soluble products released specifically from lymphocytes

Cytokines are important products in the control of immune and inflammatory responses. There are a large variety of cytokines which are produced by the body.

The action of cytokines may be autocrine or paracrine, but not endocrine. The reason for them not being endocrine signals is that the signal must be released in the general region of the pathogen-infected cells, so other immune molecules which follow the signal will arrive at the site of signal release. Cytokines are critical to the development and functioning of both the innate and adaptive immune response, although they are not limited to the immune system. They are often secreted by immune cells that have encountered a pathogen, thereby activating and recruiting further immune cells to increase the system’s response to the pathogen.

 

 

APC and CD4 Positive (T-Helper cells) Interaction

Antigen recognition by CD4 – cells requires a series of molecular interactions with APC including that between TCR (T-cell receptors, the molecules found on the surface of T cells that is, responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules) and peptide/MHC, as well as between CD4 and MHC and a range of adhesion molecules.

The consequences of T-cell activation are:

• The resting T-cell is transformed into a blast cell
• This causes the expression of activation markers (which includes IL-2 receptors)
• The blast begins to synthesise IL-2 or IL-4 which are autocrine factors
• The blast cell begins to proliferate by cloning which generates effector cells or memory cells for the specific antigen.

T-Helper Cell Types (CD4)

The T-cell can be divided into cytotoxic T-cells or helper T-cells, (CD8 or CD4 positive cells). T-helper cells can also be divided further into TH1 and TH2 cells.

• TH1 – Promote cell mediated immunity
• TH2 – Aid humoral immunity

These functions are determined by the cytokines which they secrete:

• TH1 secrete – IL-2 and IFNγ (Interferon-gamma)
• TH2 secrete – IL-4-6/IL-10

As neither of the cytokines produced by these T-helper cells overlap, the two sub-types of T-helper cells are mutually antagonistic, so in any situation it is the balance between the two subtypes of T-helper cells which determines which arm (humoral or cellular) of the immune system is promoted.

Cytotoxic T-cells (CD8)

Cytotoxic T-cells are responsible for the destruction of cells which display incompatible MHC on their surfaces. They are also able to kill virally infected host cells. Their interaction with these cells is similar to that between T-helper cells in that the target cells present an antigen in association with MHC (However it is MHC class I). This then binds to the T-cell antigen receptor and the CD8 molecule on the surface of the T-cell. The result is a lysis of the target cell

Cytotoxicity

Whilst phagocytes kill/destroy any foreign contaminant in their phagolysosomes after engulfment, the mechanism of the specific immune response is to kill by extracellular processes. This mechanism involves the recognition, adhesion and exocytosis of granules which releases various cytolytic molecules that destroy the target cell.

B-Cell Interactions

Surface immunoglobulins on B-cells are able to recognise specific antigens; this can trigger the proliferation of B cells. This differs from T-cells which recognise antigen peptides expressed on the surface of APC associated with MHC class II. The stimulation of TH2 cells and their subsequent release of cytokines provide help for B cell differentiation, antibody production (for opsonisation) and class switching (i.e. the switching of immunoglobulin type, for example IgM being switched to IgG).

Killer (K) Cells

Killer cells have FcR (The Fc receptors for binding the Fc site of antigens) which bind and kill target cells if they are coated with IgG (which provides to Fc component for binding with FcR). The resulting destruction of target cells is performed extracellularly.

NK Cells

These are lymphoid cells which have cytotoxic effects, but unlike killer cells above do not show any antigenic specificity. Instead they recognise molecules which are expressed on the surface of tumour cells. Similarly to killer cells they perform cell destruction extracellularly.

Immune Memory

After an initial response to a pathogen, the next time the body encounters that pathogen there is a much faster and stronger response. This is known as immunological memory. It is activated by the re-introduction of an antigen, and is believed that after the initial infection a constant pool of leukocytes with specificity for that antigen are stored in the body.

Regulation of the Immune Response

After the infection, the immunological response must be deactivated otherwise this may cause harm to the body. One way in which the body regulates this is to measure the concentration of antigens in the body. If the concentration of an antigen is low then there is a reduction of stimulation and hence a reduction in the immune response.