B Cells As T Cell Receptors example essay topic

'A fundamental requirement of the immune system is that it destroy, eliminate or inactivate all foreign viruses, bacteria and parasites without destroying self-cells or molecules' (Lydyard 2000). This is carried out by B and T cells, which are able to distinguish what is 'foreign' (i.e. non self) from what is self. They are responsible for the adaptive immune response and have developed a number of different mechanisms in the central and peripheral lymphoid organs that underlie the basis for self-non-self discrimination. B and T cells are derived from the lymphoid progenitor cell and possess similar characteristics such as a large nucleus and small amount of cytoplasm, however their development processes differ in a number of important ways, the most notable being that B cells develop in the bone marrow whereas T cells migrate from the bone marrow to differentiate in the thymus. Once at the correct site both cell types undergo gene rearrangements to produce a unique antigen receptor on each cell. Figure 1: Development and differentiation of a B cell.

Progenitor T cells differentiate into functional T lymphocytes under the influence of thymic stromal cells and cytokines. As seen in figure 1 the earliest recognisable B cell is referred to as a pro B cell and its specificity for a single immunoglobulin is determined by the variable region of the immunoglobulin light and heavy chains that bind to the antigen. As explained by Riot t (1998) and Janeway (1999) the variable region is encoded by sets of gene segments, which are brought together by a process known as somatic recombination. The first gene rearrangement that produces the heavy-chain immunoglobulin gene segments (DH joins JH). The next stage is the differentiation of pro into pre B cells and this requires the micro environment provided by the bone marrow stromal cells.

Here we see the joining of VD JH chains causing the heavy chain to be expressed on the cell surface with a surrogate light chain producing the expression of Mu ( ) chains. It should be noted that the V (D) J recombinase system also operates in T cells where the same core enzymes recognize the same conserved recombination signal sequences, for the T cell receptor genes (Janeway 1999). The next stage is the formation of the immature B cells. Here we see the product of light chain rearrangement replacing the surrogate light chain forming a complete IgM molecule, which is expressed on their cell surface. During differentiation, B cells are able to produce other isotopes of immunoglobulin through a process known as isotope switching whereby the class of the immunoglobulin can be switched by recombination between special switch regions that are present next to the gene of each heavy chain (Janeway 1999).

When B cells are exposed to antigen and T helper cells that secrete cytokines / lympho kines they are able to proliferate and differentiate into memory B cells and plasma cells. Both B and T cells are able to become memory cells. Figure 2: Development and differentiation of T cells As described by Janeway (1999), Progenitor T cells differentiate into functional T lymphocytes under the influence of thymic stromal cells and cytokines. This takes place when they enter the thymus in the outer cortex. At this point they express no T cell receptors and lack T cell specific co-receptors such as CD 4 and CD 8.

For this reason they are termed 'double negative' cells (CD 4-/CD 8-), although they express other markers such as CD 44 and CD 25. Once the T cell receptor gene rearrangement has been established in the subcapsular region, CD 44 loses its expression. The sequence of gene rearrangements in thymocytes is similar to that of developing B cells. The T cell receptor -chain rearrangement occurs first, followed by -chain rearrangements. As in antibodies, D - J rearrangement proceeds V - DJ rearrangement. In early T cell development we see T cell receptors for and, which express CD 3 but these only account for about 1-5% of the total T cell population.

The next stage of development is the expression of either CD 4 or CD 8. At this point the developing thymocytes are referred to as 'double positive' as they express both CD 4 and CD 8 as well as alpha ( ) and beta ( ) receptors. It has been proposed that 'a cell that has a receptor for MHC I molecules receives a survival signal and a maturation signal that makes it stop expressing CD 4 and start expressing genes characteristic of cytotoxic CD 8 T cells' (Immunobiology animations CD, 5 e Janeway - T lymphocyte development). On the other hand if a cell has a receptor for MHC II molecules they get a survival and maturation signal causing the down regulation of CD 8 and the expression of CD 4 helper T cells (CD 8- CD 4+ T cells). Allelic exclusion applies to the ability of mature T and B cells to express a single antigen receptor.

This process takes place in both cell types and is vital for the discrimination of self-non-self antigens. A B cell receptor is composed of membrane immunoglobulin, which is made of two heavy chains and two light chains that bind to two antigen molecules. T cell receptors differ to B cell receptors as they express - or / T cell receptors. In principle you would expect several antigen specificities to result due to assembly on the cell membrane of different heavy and light chain pairs (B cells) or different and chains (T cells) but because of evolution, the second allele is inactivated when the first one has completed a successful rearrangement.

The T cell receptor has a different structure to B cells and can only recognise antigen in conjunction with the Major Histocompatibility Complex (MHC). As proposed by Lydyard (2000), central tolerance occurs in the thymus whereby self-reactive T cells are eliminated by negative selection therefore preventing autoimmunity. This is essential because releasing self-reactive T and B cells into the periphery would be disastrous. The process of positive selection is initiated whereby T cells with receptors that bind weakly to MHC class I and II antigens are ignored and allowed to live by receiving a survival signal. Lydyard suggested that cortical epithelial cells that express class I MHC antigens govern positive selection.

Those thymocytes that recognise MHC I and MHC II peptides to avidly receive a strong signal that drives them into cell death - apoptosis. This is known as negative selection and leads to the elimination of some but not all self-reactive T cells and is carried out by macrophages and dendritic cells that express both MHC class I and II antigens. It should be noted that thymic selection is far stricter then bone marrow selection as there is 90% of B cell death compared to 97% of T cell death. The process of negative selection is also exemplified in B cells and takes place in the primary lymphoid organ. The bone marrow plays a very similar role to the thymus. It produces large amounts of B cells each possessing a unique antigen receptor (immunoglobulin), each specific to recognizing microbial antigens therefore generating diversity.

'B cell tolerance occurs as a result of clonal deletion, through apoptosis (Lydyard 2000/147) whereby self-reactive lymphocytes are eliminated on contact with self-antigens through expression of Fas (receptor protein). T lymphocytes express Fas and Fas. Another important process that occurs to B cells is that immature, self-reactive B cells can escape death if they rearrange their immunoglobulin genes. This is known as receptor editing. In doing this, only B cells that don't react with self antigens are allowed to migrate to the periphery and mature expressing Igm in addition to IgM (antigen receptors). An important point is that tolerance is easier to induce in T cells than in B cells, and once it has gained this so called 'tolerance', it lasts longer (Lydyard 2000).

Once B and T cells have gone through central tolerance mechanisms in the primary lymphoid organs, they have gone through maturation, where they have acquired tolerance to self-antigens. Even though the selection process eliminated the majority of self-reactive lymphocytes not all were destroyed in the primary lymphoid organs. There are two reasons for this, firstly self antigens are not all located in the primary lymphoid organs and secondly, different receptor expression / specificities may occur due to somatic mutation of the antibody genes. This is known to occur only to B cells, as T cell receptors do not usually mutate. However, there are several mechanisms whereby B and T lymphocytes acquire peripheral tolerance to self-antigens in the peripheral tissues. These mechanisms proposed by Lydyard include elimination, anergy and activation induced death.

'Anergy is a state of non-responsiveness to antigen' (Janeway, Travis and Walport 1999: 594). It is the main mechanism by which T cells are made tolerant. T cell anergy is associated with na " ive T cells, as they require two signals to respond to an antigen. If either signal is not there the T cell becomes anergic. B cells can also be anergic and require T cell help in order to develop into plasma cells. B cells need to engage with certain molecules from T cells and certain cytokines to become activated; therefore any absence of these molecules causes them to become anergic.

So in conclusion, both B and T cells have essential roles to play for the basis of self-non-self discrimination and they carry out these roles through mechanisms of central tolerance and peripheral tolerance. From books: P.M. Lydyard, A. Whelan and M.W. Finger (2000) Instant Notes in Immunology BIOS Scientific Publishers Limited o Section K, L, M o 'A fundamental requirement of the immune system is that it destroy, eliminate or inactivate all foreign viruses, bacteria and parasites without destroying self-cells or molecules' (section M 1). o 'B cell tolerance occurs as a result of clonal deletion (apoptosis), through apoptosis' (M 2). J.R. Inglis (1982) B LYMPHOCYTES TODAY. Elsevier Biomedical Press (63-69) J.R. Inglis (1983) T LYMPHOCYTES TODAY. Elsevier Biomedical Press (66-69) From textbooks: Janeway CA, Travers P, Walport M (1999) IMMUNOBIOLOGY 4 e (chapters 6-7) o 'Anergy is a state of non-responsiveness to antigen' (594) Klein J, Horejsi V (1997) Immunology 2 e From World Wide Web: B lymphocyte differentiation web Immunobiology 5 animations web 'A cell that has a receptor for MHC I molecules receives a survival signal and a maturation signal that makes it stop expressing CD 4 and start expressing genes characteristic of cytotoxic CD 8 T cells' Figure 1 web Figure 2 web Self and Non-self discrimination (2001) web B lymphocyte differentiation web.