OBAI TIFFANY BWARI
BONUS INDIVIDUAL ASSIGNMENT-PAT3371
Lymphocytes are the smallest and second most abundant type of white blood cells. They have a large round, nuclei that covers most of the cell leaving room for only little cytoplasm. They are known as the cells of immunity and function mostly to illicit a specific response against foreign antigens. There are two types of lymphocytes, T and B lymphocytes, on which the immune system depends upon. The development of lymphocytes involves transcription of several transcription factors. Both the T and B lymphocytes are derived from the hematopoietic stem cell. The development of lymphocytes begins as the earliest branch of the hematopoietic stem cell. The hematopoietic stem cell can develop into common lymphoid progenitor (CLP) or common myeloid progenitor (CMP). The common lymphoid progenitor then will produce T and B lymphocytes while CMP produces myeloid elements. So, lymphocytes originate from CLP in the bone marrow just like all hematopoietic cells. It is important to note that during postnatal life, the bone marrow and thymus are the primary/central lymphoid organs while the secondary lymphoid organs in which specific immune response take place are the lymph nodes, spleen and lymphoid tissue. (Samuel, n.d.) Lymphopoiesis, takes place in specialized lymphoid tissues, the central lymphoid tissues, which are the bone marrow in the case of B cells and the thymus for T cells. B cells complete most of their development within the bone marrow while T cells are generated in the thymus from precursor cells (T cell progenitor) that originated from the bone marrow. (Janeway CA Jr, 2001)
They originate in the bone marrow and once mature they circulate in the peripheral blood until they recognize an antigen. Their development is altered by cytokines including IL-7 which interacts with stem cell factor to begin the process. The stages in B-cell development include the hematopoietic stem cell (HSC), then common lymphoid progenitor, pro-B cell, pre-B cell, immature B cell and finally the mature B cell. In order for these cells to function they display immunoglobulins on their surface. It begins at the pro-B cell stage and is needed for the development and maturation of B lymphocytes from the common lymphoid progenitor to the pre-B cell. The sequence of immunoglobulin expression on the surface of B lymphocytes includes IgM, then IgD and finally IgG or IgA. The termination of B-cell development occurs in the peripheral lymph organs such as the spleen and the lymph nodes in which they are converted to plasma cells or memory cells. The role of plasma cells is the synthesis and secretion of antibodies while that of the memory cells is to remember antigens to which it has been exposed to in the past. (Samuel, n.d.)
As noted, “one of the key roles played by the B cells in an immune response is the production of antibodies, that specifically recognize and bind to proteins on the invading bacteria or virus particles. This can prevent viruses from entering cells or aid phagocytes in identifying and destroying the bacteria or viruses. Given that each B cell can only produce antibody with one specificity, and that there are an enormous variety of organisms that can infect us, the immune system needs to generate vast numbers of B cells that each produce a different antibody. The specificity of a particular antibody is determined by the shape of its variable region; a particular antibody will bind to a protein that has a region with a complementary structure to the antibody’s own variable region. Diversity in the specificity of antibodies is initially generated at the earliest stages of B-cell development. While still at the B-cell progenitor stage in the bone marrow, B cells randomly rearrange their variable (V), diversity (D), and joining (J) genes to form the blueprint for the variable regions of their antibodies. Diversity comes from the fact that there are multiple copies of the V, D and J genes that can be joined together in different combinations. In a majority of mammals, each antibody molecule is composed of both a heavy and light chain, which each have their own V and J genes to rearrange (only the heavy chain has D genes). Further diversity is added to the variable region genes by an enzyme called terminal deoxynucleotidyl transferase (TdT) that adds extra nucleotides between the V, D and J regions, changing the structure of the variable regions that will be produced. During the course of an infection, B cells can further alter the specificity of the antibody they produce. When a mature B cell meets an antigen that its B-cell receptor recognizes (the B-cell receptor comprises the antibody the cell produces anchored on the cell surface) then the B cell can undergo a process called somatic hypermutation. Here an enzyme called activation-induced cytidine deaminase (AID) makes random mutations in the antibody variable region genes. If the mutations result in an antibody that more strongly binds to their targets then these B cells will survive and may differentiate into antibody-producing plasma cells with the new specificity.” (Bosma)
T- Lymphocyte development begins with common lymphoid progenitor cells that migrate to the thymus where they will differentiate into mature T cells (Samuel, n.d.).These cells are also called thymocytes. Developing thymocytes interact with the thymus non-hematopoietic/stromal cells, and undergo development in distinct regions of the thymus. It is associated with the movement of the cells through the cortex and medulla of the thymus. (Shah) Maturation starts in the cortex, and as the cells continue to develop, they move towards the medulla. During the stages of T cell development, the cells contain specific surface proteins. As the cell progresses through maturity, these proteins are used as cell surface markers by antibodies in order to identify the T cell. These different cell markers also enable identification of the different maturation steps involved in the development of these cells. T cells eventually differentiates into two types of T lymphocytes: killer T-cell and helper T-cell. Killer T-cells are important because they synthesize lymphokines which help B cells to destroy foreign substances. Killer T-cells also have CD8 antigen. Helper T-cell on the other hand produces CD4 antigen and functions to assists killer T cells with the protection of the body against invading organisms. Like B-cells, T-cells depend on IL-7 and other interleukins. It is important to note that most of T-cell development occurs in the thymus; however, the final steps in the production of mature killer and helper T-cell occur in the peripheral blood just like those of the B cells (Samuel, n.d.). The development of T lymphocytes constantly addresses the dilemma of generating T cells specific to a varied number of pathogens, to combat infection without provoking a response to the host. T lymphocytes are thus subjected to a rigorous selection process during development in the thymus to delete self-reactive T cells thus preventing cases of autoimmunity even as these lymphocytes are produced against such a varied range of antigens. In addition, premature activation of mature peripheral T cells is prevented by requiring two signals in order for the T lymphocytes to be activated. Finally, the expansion of T cell numbers that occurs during either normal proliferation in the periphery or in response to an infection is resolved by the active induction of cell death. The consequences of inefficient lymphocyte removal at any one of these junctures can be devastating to the health of the organism. (Fortner, 2017)
As observed, “The earliest developing thymocytes don’t express the co-receptors CD4 and CD8 and are termed double negative (DN) cells. The DN population can be further sub-divided by the expression of CD44 (an adhesion molecule) and CD25 (Interleukin-2 receptor ? chain). Cells that lack expression of CD44, but express CD25 (DN3) undergo a process termed beta-selection which selects for cells that have successfully rearranged their TCR-? chain locus. The ? chain then pairs with the surrogate chain, pre-T?, and produces a pre-TCR, which forms a complex with CD3 molecules. This complex leads to the survival, proliferation, arrest in further ? chain loci rearrangement, and further differentiation by up-regulation and expression of CD4 and CD8, these cells are termed double positive (DP) cells. Cells that do not undergo beta-selection die by apoptosis. DP cells rearrange their TCR-? chain loci, to produce an ??-TCR. These cells then undergo positive selection, in the cortex. DP cells interact with self-antigens in the context of major histocompatibility complex (MHC) class I or class II molecules. Those cells that engage antigen/MHC with an appropriate affinity survive, whereas those cells that interact with a weaker affinity die by apoptosis. Thymocytes then migrate into the medulla to undergo negative selection. They are presented self-antigens on antigen presenting cells (APCs), such as dendritic cells and macrophages. Thymocytes that interact too strongly with antigen undergo apoptosis. The majority of developing thymocytes die during this process. Following selection, down-regulation of either co-receptor produces either naïve CD4 or CD8 single positive cells that exit the thymus and circulate the periphery.” (Shah)
Bosma, P. A. (n.d.). Generation of B-cell / antibody diversity. British society of immunology.
Fortner, R. c. (2017). T lymphocytes. In R. C. Gary S. Firestein, Kelley and Firestein’s book of rheumatology (10 ed., Vol. 1, pp. 189-206). Philadelphia, PA: Elsevier. doi:https://www.sciencedirect.com/science/article/pii/B9780323316965000127
Samuel, L. (n.d.). Lymphopoiesis: The development of lymphocytes. Retrieved from interactive biology: http://www.interactive-biology.com/3998/lymphopoiesis-the-development-of-lymphocytes/
Shah, D. K. (n.d.). T cell development in the thymus. British society of immunology.
Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. Chapter 7, The Development and Survival of Lymphocytes. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10761/