T and B lymphocytes.pdf

 Acquired immunity is characterized by 1- High specificity to antigens. 2- Require prior exposure to antigen. 3- Development of immunological memory, that is why primary IR is weak while secondary IR is rapid and strong. 4- Wide diversity to different antigens.  CELL-MEDIA...

 Acquired immunity is characterized by 1- High specificity to antigens. 2- Require prior exposure to antigen. 3- Development of immunological memory, that is why primary IR is weak while secondary IR is rapid and strong. 4- Wide diversity to different antigens.  CELL-MEDIATED IMMUNITY (CMI)  T-lymphocytes (T cells) produce cytokines. ANTIBODY-MEDIATED (HUMORAL) IMMUNITY  B-lymphocytes (B cells) produce immunoglobulins (antibodies)  T Lymphocyte development -The lymphoid system is composed of primary lymphoid organs as bone marrow and thymus (haemopoiesis, lymphopoiesis and maturation of lymphocytes) and secondary lymphoid organs as lymph nodes, spleen and tonsils (naïve mature lymphocytes will be exposed to their specific antigens) -All the cells of the immune system arise from Hematopoietic stem cells (HSCs), in the bone marrow that differentiate into cells of lymphoid or myeloid progenitors. The lymphoid stem cells differentiate into B lymphocytes, T lymphocytes and NK cells while the myeloid stem cells differentiate into monocyte- macrophages, eosinophils, mast cells and neutrophils. T cell ontogeny (development inside the thymus)  T Lymphocyte Development originates from stem cells in bone marrow followed by migration to the thymus gland where they undergo several steps of maturation.  In the thymic cortex: 1- Pro-T cells: rearrangement of T cell receptor (TCR) genes 2- Pre-T cells: The β chain of TCR is rearranged and expressed first (pre- TCR). 3- Survived T cells then express the complete Ag receptors and CD3. (For reading only: The T cells acquire specific TCR to a single specific antigen and responding only to that antigen to produce clone of cells of the same specificity to that antigen (Clonal Selection) 4- They express both CD4 and CD8 (double positive immature T cells). In the medulla of thymus: Positive selection - Promotes survival of T cells whose TCRs can recognize self peptide with weak affinity and are able to recognize foreign peptide antigens in peripheral tissues. - Generation of T cell subsets: - Immature T cells that express both CD4 and CD8 differentiate into either CD4+ T cells or CD8+ T cells. - Negative selection (central tolerance): - leads to deletion (by apoptosis) of immature T cell clones whose TCRs bind strongly to self antigen present in the generative lymphoid organs (Clonal deletion). - This will eliminate the potentially most harmful self reactive T-cells and maintain central self tolerance. - Naïve Mature immunocompetent T cells pass to circulation and peripheral lymphoid tissues -  Structure of T cell Antigen Receptor (TCR) - TCR-2 formed of 2 peptide chains designate α and β. - The amino terminal domains of α and β (α1 and β1) are pleomorphic (V domains) and form the antigen binding site. - The carboxy terminal domains (α2 and β2,) are constant (C domains). - α/β dimer is associated with a complex of proteins; CD3, (For reading only: CD3 is formed of 4 peptide chains γ, δ, 2ε, and 2 zeta (ζ)chains. CD3 is essential for surface expression and stability of TCR and for transduction of signal of activation to inside the cell (signaling chains). B Lymphocyte development  Structure of B cell Antigen Receptor (BCR): - Single molecule of IgM expressed on the surface of B cell (together with IgD in case of mature B cells) (membrane Ig, mIg). - Ig-α/Ig-β heterodimers are associated with the mIg subunits. - The mIg is formed of 2 heavy and 2 light chains. - The light chain contains one variable and one constant domain. (For reading only: There are 2 types of light chains; kappa (ĸ) and lambda (λ). The light chains in a single molecule of Ig are of the same type, never both together). - Heavy chain contain one variable and 3 constant domains. - Variable regions of both heavy and light chains form the antigen binding site. Steps of B cell maturation in Bone Marrow (ontogeny) 1-Pro-B cells - The first recombination of Ig genes occurs at the heavy chain locus. 2-Pre-B cells - Express the heavy chains mu (μ) of IgM to form the pre- BCR. 3-Immature B cells - Express a single molecule of IgM, formed of 2 heavy and 2 κ light chains. (For reading only: If the κ locus is not productively rearranged, the cell can rearrange the λ locus and produce a complete IgM molecule). 4- Positive selection: - B cells that express functional membrane Ig molecules receive survival signals 5-Negative selection: - B cells that express receptors with high avidity to self antigens that are present in the bone marrow undergo cell death (clonal deletion). 6- Mature B cells: -Immature B cells that are not self-reactive leave the bone marrow and complete their maturation in the spleen before migrating to other peripheral lymphoid organs. Mature B cells express IgM and IgD as Ag receptors. -Mature B cells are activated, change to plasma cells which secrete thousands molecules of specific antibodies, leading to humoral immune responses.  Subsets of Mature B Cells (For reading only): Follicular B cells - Most mature B cells belong to this subset and express IgD in addition to IgM. - They are also called recirculating B cells because they migrate from one lymphoid organ to the next, residing in the B cell follicles. Marginal zone B cells - Located in the marginal sinus in the spleen and in lymph nodes. - They are of limited diversity, respond rapidly to blood-borne microbes and differentiate into short-lived IgM-secreting plasma cells. B lymphocyte subsets Cell mediated immunity (CMI) Antigen presentation and Major histocompatibility (MHC) molecules  Professional Antigen presenting cells (APC’s) -Macrophages -Dendritic cells -B lymphocytes Ingest and process antigens then display fragments (short peptides) on their surface in association with molecules of major histocompatibility complex (MHC). MHC antigens - Group of proteins expressed on the surface of all body cells - Also called human leucocytic antigen HLA because they were first discovered on human leucocytes. - MHC proteins are classified into 2 classes; Class I and Class II MHC class I: - Expressed on the surface of all nucleated body cells Structure of Class I antigens: - A heavy chain molecule non-covalently associated with a small molecule, β2 microglobulin - consists of 3 extracellular domains (α1, α2, α3), a transmembrane region and a cytoplasmic tail. - The groove between α1 and α2 form the peptide binding site. MHC class II: - Expressed only on immune cells. Structure: - 2 polypeptide chains, α and β, the extracellular region of each chain folds to form 2 domains; α1, α2 and β1, β2. - Peptide binding site is formed by α1 and β1.  Antigen processing and presentation: 1- Endocytic (class II, exogenous) pathway: - Extracellular microbes or their products are internalized into the vesicular compartment of APCs where they are degraded by enzyme in endosomes to generate peptides. - These peptides are delivered to MHC class II molecules which are expressed by APCs that present antigens to CD4 TH cells (Class II MHC restricted). 2- The cytosolic (class I, endogenous) pathway: - Endogenously synthesized proteins in the cytosol of nucleated cells as intracellularly synthesized microbes mainly viruses are proteolytically degraded to peptides. - The peptides are delivered to MHC class I expressed on all nucleated body cells and present CD8 (Tc) cells (Class I MHC restricted). Antigen Presentation  MHC / T cell interactions Peptide binding cleft 2 1 1 1 3 2-microglobin 2 2 Class II MHC Class I MHC Class II MHC target cell Class I MHC Antigen presenting cell CD8 CD4 CD8+ T cell TCR complex TCR complex CD4+ T cell CD4 T-cells are MHC II restricted and only recognize specific foreign peptide only when they are presented in association with specific MHC II molecules * CD8 T-cells are MHC I restricted and recognize specific foreign peptidees only when they are presented in association with specific MHC I molecules  The antigen processing pathways Endocytic pathway Cytosolic pathway MHC utilized Class II Class I Major Ag source Extracellular proteins cytosolic proteins of host or intracellular pathogen, viral, bacterial, fungal or parasitic. Processing Lysosomal enzymes Proteasomes machinery in the lysosomes. Cell type where Professional APCs All nucleated cells active Presentation to T helper cells T cytotoxic cells.  Types of T cells - T cells are divided into 2 subsets: 1- A subset carries CD4 marker, T helper (TH, T4) cells which is divided into different types: TH1, TH2, TH17 and Regulatory T cells (Tregs) All arise from the same precursors, the näive TH0 cells 2- A subset carries CD8 marker, T cytotoxic (T8) cells.  Activation of T cells The principle orchestrators of the immune response as they are needed for the activation of the major effector cells in the immune response:  Macrophages  Cytotoxic T cells (CD8)  Antibody producing B lymphocytes Two signals are required to activate T cells: First signal: Antigen recognition: The initial activation of naive T lymphocytes occurs mainly in secondary lymphoid organs, where they may encounter antigens presented by mature APCs. (Class II MHC + antigen – TCR)  Second signal: (Costimulatory signal) 1-The B7: CD28 Family of Costimulators: Cell surface receptor CD28 on lymphocyte, binds the costimulatory molecules B7 expressed on activated APCs. 2- Role of CD40L and CD40: - The interaction of CD40L on activated T cells with CD40 on APCs. Role of CD40L and CD40 3- The Role of the CD4 and CD8: - Interaction of CD4 or CD8 on TH and TC cells with constant regions of class II (β2) or class I (α3) MHC on APCs also send signal of activation. -The final result is the expansion of the T cell clone specific to the activating Ag (clonal expansion). - Primary immune response results in: 1- Development of effector T cells. 2- Development of memory cells  Migration of effector T cells to sites of infection Effector T cells express adhesion molecules and chemokine receptors that allow them to migrate through blood vessels to the site of infection.  1- Functions of TH1 cells: - IL-12 (by activated dendritic cells and macrophages) and INF-gamma (by NK cells) (early innate immune response) induce the differentiation of naive TH0 to the TH1 subset. - Activated TH1 secrete IFNγ, TNF-β, IL2. - IFNγ: is the signature cytokine of TH1 and is critical in immunity against intracellular microbes. as M. tuberculosis, Listeria monoctogenes, Legionella and some protozoa. These enhance  T-cytotoxic (Tc)  Activates macrophages to ingest and destroy microbes.  Acts on B cells to promote switching to certain IgG subclasses that participates in opsonization and antibody dependent cellular cytotoxicity (ADCC).  2- Functions of TH2 cells: - IL-4 produced by mast cells and eosinophils, especially in response to helminths and allergens induce the differentiation of TH0 cells to the TH2 subset. -TH2 cells stimulate IgE- and eosinophil-mediated reactions that serve to eradicate helminthic infections. Cytokines Produced by TH2 Cells: IL4 (the signature cytokine), 5, 6, 10 and 13. 1- Immune response against Helminthes: IL-4 (and IL-13) stimulates the production of helminthes- specific IgE antibodies, which attach to helminthes and promote the binding of eosinophils. IL-5 stimulate activation of eosinophils to release their granule contents, which are capable of destroying even the tough teguments of helminthes 2- Activation of mast cells: Mast cells express Fc receptors and is activated by IgE-coated helminths, resulting in degranulation and release of vasoactive amines, TNF and chemokines, and lipid mediators, all of which induce local inflammation that helps to destroy the parasites. 3- Barrier immunity: IL-4 and IL-13 stimulate mucus production and peristalsis in the gastrointestinal system leading to elimination of microbes at epithelial surfaces. 4- Tissue repair and fibrosis: IL-4 and IL-13 activate macrophages to express enzymes that promote collagen synthesis and fibrosis. Functions of TH2 cells  3- Functions of TH17 Cells -IL-6 , IL-1 and TGF-β produced by dendritic cells and macrophages stimulate the differentiation of naive TH0 to the TH17 subset. -The principal effector function of TH17 cells is to induce neutrophilic inflammation, which serves to destroy extracellular bacteria and fungi. Cytokines Produced by TH17 Cells Interleukin-17  Induces neutrophil-rich inflammatory reactions. It stimulates the production of cytokines (such as TNF, IL-1, IL- 6) that recruit neutrophils to the site of T cell activation.  Il-17 stimulates the production of antimicrobial substances, including defensins. IL-22 Produced in epithelial tissues and serves to maintain epithelial integrity and stimulates repair reactions. Il-21 Increases the proliferation and effector function of CD8+ T cells and NK cells. Functions of TH17  4- Regulatory T Cells (Treg cells) Function: - Secrete immunosuppressive IL10, TGF-beta that suppress immune response; Cell-mediated and Ab- mediated. - Maintain the peripheral self tolerance by suppressing the autoreactivity T cells that escape the thymus and inhibiting them from mounting an immune attack against self components; that is, to protect the body against autoimmunity.  Activation of Tc cells (CTLs): CD8+ CTLs eliminate intracellular microbes mainly by killing infected cells. - Respond to Ag in combination with class I MHC which is expressed on all nucleated cells. - Important in defense against virus infection by directly killing virally infected cells. - Involved in IR to some intracellular bacteria. - Play role in IR to tumor by killing malignant cells.  Mechanisms of killing target cells: 1- Perforin and granzyme effect. -Perforin form pores in the cell membrane to facilitate delivery of the granzymes into the cytoplasm of the target cell. -Once in the cytoplasm, the granzymes activate caspases, and initiate apoptotic death of the cell. 2- Fas-Fas ligand. - CTLs express a membrane protein, called FasL, that binds to the death receptor Fas, which is expressed on many cell types. -This interaction results in activation of caspases and apoptosis of Fas-expressing targets by degrading DNA.  Memory T cells Are a subset of T cells that have previously encountered and responded to their cognate antigen (antigen-experienced T cell). At a second encounter with the invader, memory T cells can reproduce to mount a faster and stronger immune response  Natural Killer Cells Cytokines: IFNy and TNFα. Role in IR: 1- Part of innate immunity, naturally kill tumor cells and virally infected cells. 2- Like CTL, use perforins & granzymes to kill target cells.  NK cells differ from CTLs in 1) They are non-specific 2) They act spontaneously without prior recognition or activation 3) They do not require antigen presentation by MHC 4) They destroy cells coated with antibodies, a mechanism called antibody dependant cellular cytotoxicity (ADCC)