T and B Lymphocytes PDF

T and B lymphocytes By Dr. Hanan Mazin Sedeeq F.I.B.M.S /Microbiology and Clinical immunology E-mail :[email protected] Objectives At the end of this lecture the student should be able to : 1) know the origin and maturation of T and B lymphocytes. 2) Des...

T and B lymphocytes By Dr. Hanan Mazin Sedeeq F.I.B.M.S /Microbiology and Clinical immunology E-mail :[email protected] Objectives At the end of this lecture the student should be able to : 1) know the origin and maturation of T and B lymphocytes. 2) Describe the receptors of T and B cells. 3) Classification of the T cells. 4) Define naïve lymphocyte, plasma cell and memory cell. 5) Understand the clonal and thymic selection. 6) Enumerates the functions of T and B cells. 7) Mention the function of NK cells. Introduction Lymphocytes are a type of white blood cell. They play an important role in your immune system, which helps your body fight disease and infection. Your immune system is made up of immune cells, lymph nodes, lymph tissue and lymphatic organs. Lymphocytes are a type of immune cell. There are two main types of lymphocytes: ❖ T lymphocytes (T cells): T cells control your body’s immune system response and directly attack and kill infected cells and tumor cells. ❖ B lymphocytes (B cells): B cells make antibodies. Antibodies are proteins that target viruses, bacteria and other foreign invaders.  Adaptive immunity is mediated by T lymphocytes (or T cells, so- called because their development mainly occurs in the thymus) and it is responsible for cellular immunity and B lymphocytes (or B cells, so- called because their development mainly occurs in the bone marrow) and it is responsible for humoral immunity. Unlike innate immune cells, T cells and B cells recognize antigens, rather than universal microbial “patterns.” Origin of lymphocytes  T lymphocytes T-cell precursors derive from common lymphoid progenitors. But unlike B cells, T-cell development includes a step in which the precursors migrate through a specialized organ called the thymus. It is during passage through the thymus that a T-cell precursor begins to express a unique TCR, and upon exiting the thymus, they are called mature naïve T cells because at this stage they have never seen foreign antigens Development of naïve lymphocytes Mature T-cell with TCR What is naïve lymphocytes ??? Lymphocytes which have not met a specific antigen and therefore did not have the opportunity to be activated by antigen and subsequently be differentiated into memory and efficient cells. All lymphocytes that leave the central lymphoid organs are naïve. The naïve lymphocytes differentiated into either effector cells or memory cells which is initiated by antigen recognition, thus ensuring that the immune response that develops is specific for the antigen. T cell receptor structure TCRs have analogous chains but only have two chains instead of four. the TCR is composed of a single α (alpha) chain and a single β (beta) chain. Each chain includes a variable region, which includes the hypervariable region that binds to the peptide–MHC complex, and a constant region, which attaches the α chain and β chain to each other. The α chain and β chain are mostly located outside the cell, and they are fixed to the cell membrane by a transmembrane domain and a short cytoplasmic tail.  The tail binds to a molecule called CD3ζ (CD3-zeta). Although it is not actually part of the antigen receptor, all T cells have CD3 proteins in association with TCR. The purpose of CD3 is to transmit the TCR peptide recognition signal from the surface to the inside of the cell. This is achieved through intracellular tyrosine kinases that are bound to CD3 and phosphorylate downstream second messengers. The CD4 and CD8 proteins are coreceptors for the TCR; they sit in the T-cell membrane and bind to nonpolymorphic regions on MHC (class II and class I, respectively). The cytoplasmic domains of CD4 and CD8 amplify the TCR signal transmission , also through a cytoplasmic tyrosine kinase. T cell receptor structure T cell receptor structure Positive and negative thymic selection Positive selection : ❖T-cell precursors arrive in the thymus cortex lacking CD4 and CD8 (double-negative) and lacking a T-cell receptor (TCR). ❖ They then become CD4+CD8+ (double-positive) while rearranging their TCR genes to generate unique TCRs. ❖ Next, double-positive cells meet specialized thymus cells expressing a wide range of self-peptides complexed with class I and class II major histocompatibility complex (MHC). ❖ Only the T cell precursors that do bind to MHC are chosen to survive. Negative selection ❖The surviving cells move into the thymus medulla, where those that make strong contacts with self-antigens are killed by apoptosis. ❖The T cells that don’t strongly bind to self peptides are allowed to survive. ❖ These cells exit the thymus as mature naïve T cells and migrate throughout the circulation and secondary lymphoid tissues surveying for antigen. Thymic selection generates mature naïve T cells Positive and negative selection  T lymphocyte cells can be further divided based on their function and based on molecules on the cell surface called “cluster of differentiation” (or CD). These proteins are important for the function of these cells and are used to distinguish them. CD 4 positive T –cell CD 8 positive (cytotoxic T lymphocytes CTL)  CD 4 positive T-cell can be divided into three main categories: (1) effector/helper (Teff or Th) cells, which leave the lymphoid organ and coordinate immune responses in inflamed tissue; (2) follicular helper (Tfh) cells, which move into the B-cell follicle of the lymphoid organ and help the B cells; and (3) regulatory T (Treg) cells, which suppress inflammation. Effector/helper (Teff or Th) cells divided into : 1. Th-1 cells. 2. Th-2 cells. 3. Th-17 cells.  CD8 positive marks the cells that are called cytotoxic T lymphocytes (CTLs) The main function of cytotoxic (CD8-positive) T cells is to recognize and kill any cell that has foreign (non self) proteins on its surface. Cells might contain foreign proteins because the cells have been infected by viruses, bacteria, or fungi.  Remember, all of these T cells require cell–cell interactions and TCR– peptide–MHC recognition, both for their initial priming and later for their effector functions. Also, after an infection is cleared, each of these T-cell types can contribute clones to the pool of memory T cells that patrol the body and respond rapidly to reinfection.  B lymphocytes B cells perform two important functions: (1) They differentiate into plasma cells that produce antibodies (also called immunoglobulins). (2) They can become long-lived memory B cells that can rapidly respond to a reinfection. ✓The immunoglobulin on the B-cell surface is its antigen receptor (B-cell receptor or BCR) and the ability of a B-cell precursor to make this antigen receptor determines whether it is allowed to develop in to a mature B cell. Origin of B-cell B-cell precursors first arise from stem cells in the fetal liver, but by the time of birth, these stem cells migrate to the bone marrow, which is their main location during childhood and adult life. Unlike T cells, B cells do not require the thymus for maturation. The maturation of B cells has two phases: ✓ the first is the antigen-independent phase, which consists of stem cells, pre-B cells, and B cells, and it is during this phase that the B cell recombines its immunoglobulin genes to make a unique antigen receptor. For pre-B cells to differentiate into B cells, a functional immunoglobulin must be present on the cell surface. A protein called Bruton’s tyrosine kinase (BTK) detects this immunoglobulin and signals to the cell to continue to divide and differentiate. A mutation in the gene encoding this protein causes X-linked agammaglobulinemia, a condition in which cells cannot progress to the pre-B cell stage and no antibodies are made. ✓ During the second phase, which is the antigen-dependent phase, mature B cells with functional antigen receptors interact with antigens. Maturation of B cells. The immunoglobulin (Ig), or BCR, of a mature B cell is an IgM molecule with an additional region at the end of its heavy chain that tethers it to the B-cell surface. B cells are produced each day, but only a small fraction of these make it from the bone marrow into the circulation, and unless they are activated through their antigen receptors, circulating B cells have a short life span (i.e., days or weeks). Mature B-cell with BCR Antibody (immunoglobulin) Structure Antibodies are glycoproteins made up of light (L) and heavy (H) polypeptide chains. The terms light and heavy refer to molecular weight; light chains have a molecular weight of about 25,000, whereas heavy chains have a molecular weight of 50,000 to 70,000  The simplest antibody molecule has a Y shape and consists of four polypeptide chains: two identical H chains and two identical L chains. One end of the Y is composed of two identical pieces that bind the antigen, and therefore, this is called the antigen binding fragment (or Fab). The Fab includes the variable region of the L chain (VL) and the variable region of the H chain (VH), as well as the constant region of the L chain (CL) and the first constant region of the H chains (CH1). Antibody structure  The portions of the L and H chains that actually bind the antigen are only 5 to 10 amino acids long, each composed of three extremely variable (hypervariable) amino acid sequences. The other end of the Y is a single stalk, where the H chains come together, and it is made of the remaining three or four constant regions of each of the H chains (CH2, etc.). This is called the constant or “crystallizable” fragment (or Fc).  You might think that the Fab is the most important part of the antibody because it binds the antigen, but the Fc is needed to attach the antibody to host cells (e.g., via Fc receptors) or to complement (at the CH2 domain). The Fc is also the region that is used to fuse IgM and IgA together into larger “multimers.” It is also necessary for transport of IgA across epithelial barriers and transport of IgG from mother to fetus through the placenta. Plasma and memory cells Plasma cells release antibodies in response to antigens. Once a B cell becomes a mature plasma cell, it can release up to 2,000 antibodies per second. Plasma cells are also called plasmacytes or effector cells. They have a shorter lifespan than memory cells.  Memory cells, also generated from the progeny of antigen-stimulated lymphocytes, do survive for long periods in the absence of antigen. Memory cells are functionally inactive; they do not perform effector functions unless stimulated by antigen. When memory cells encounter the same antigen that induced their development, the cells rapidly respond to initiate secondary immune responses Clonal Selection The first step of B-cell clonal selection is called positive selection. Pre-B cells lack surface BCR. If a B-cell precursor fails to rearrange its immunoglobulin gene segments and generate a functional BCR, it dies before it reaches the mature B-cell stage. This is called positive selection because only those cells that do generate a BCR are allowed to survive and mature.  Pre-B cells that do successfully generate surface IgM pass through positive selection and progress to become B cells. At this stage, their IgM BCRs immediately encounter self-antigens. Remember that, whereas T-cell receptors can only bind peptides complexed with major histocompatibility complex (MHC) proteins, the BCR can potentially bind to any circulating proteins, lipids, carbohydrates, or nucleic acids. However, because this phase of development occurs in the bone marrow rather than in the peripheral tissues or secondary lymphoid organs, all of the antigens that the B cell could encounter at this stage are self antigens.  During this phase, called negative selection, if the BCR strongly binds a self-antigen, this indicates high potential for autoreactivity. this cell will be removed from the pool of mature B –cell clone by apoptosis. only B cells that do not strongly bind self-antigens are allowed to leave the bone marrow and, therefore, will be self-tolerant. Comparison of T cells and B cells Functions of T cells Host defense against infection (especially Mycobacterium tuberculosis, fungi, and virus-infected cells). Tumor rejection. Coordination and regulation of adaptive immune response (helper T cells) Allergy/hypersensitivity (e.g., poison oak). Autoimmunity. Transplant graft rejection. Functions of B cells Host defense against infection (opsonize bacteria, neutralize toxins and viruses). Allergy/hypersensitivity (e.g., hay fever, anaphylactic shock). Autoimmunity. Natural killer cells Large granular lymphocytes (non B non T lymphocytes). Lack T-cell receptor, CD3 proteins, and surface IgM and IgD. Thymus not required for development. Normal numbers in severe combined immunodeficiency disease (SCID) patients. Activity not enhanced by prior exposure Have no memory Function of NK cells Recognize virus-infected cells by detecting lack of class I MHC proteins on the surface of the infected cells Kill virus-infected cells and cancer cells using perforin and granzyme Killing is nonspecific and is not dependent on foreign antigen presentation by class I or II MHC proteins Produce gamma interferon that activates macrophages to kill ingested bacteria  Summary T and B lymphocytes are important component of adaptive immunity. Mature naïve T cell is a T cell with unique TCR. Mature naïve B cell is a B cell with BCR IgM and IgD immunoglobulin Naïve lymphocytes never met a specific antigen The effector cells in the B lymphocyte are antibody-secreting cells, called plasma cells. The effectors cells in T lymphocytes are helper and cytotoxic T lymphocytes.  References Review of Medical Microbiology and Immunology -fifteenth edition. Basic Immunology –seven edition.