Cells and Tissues of the Immune System

Lymphocytes • circulation / various lymphoid organs • Number in humans :1012 • Diversity of antigen recognition (recognizing • tens or hundreds of millions of antigens) Somatic rearrangement of antigen receptor genes during lymphocyte maturation • T- lymphocyte • B - lymphocyte T Lymphocytes • T lymphocytes generated in the thymus. • Mature T cells 60%- 70% of lymphocytes in blood • T cells location : Peripheral blood, T-cell zones of • • • • peripheral lymphoid organs (splenic periarteriolar sheaths and lymph node interfollicular zones ) The isolation of naive T cells to these anatomic sites is because the cells express receptors for chemokines that are produced only in these regions of lymphoid organs. Each T cell is genetically programmed to recognize a specific cell-bound antigen by means of an antigen-specific T-cell receptor (TCR). T cells do not detect free or circulating antigens. The vast majority (greater than 95%) of T cells recognize only peptide fragments of protein antigens bound to proteins of MHC. T-cell receptor (TCR) In 95% of T cells TCR: consists of a disulfidelinked heterodimer made up of an α and a β polypeptide chain. variable (antigen-binding) region:Peptide Ag (MHC ) signal : constant region costimulator molecules (B7) Each TCR is noncovalently linked to a cluster of five polypeptide chains : 1) CD3 molecular complex 2) two dimer of chain. They do not bind antigen , transduction of signals into the T cell after the TCR has bound the antigen. The TCR γ, δ recognizes peptides, lipids, and small molecules, without a requirement for display by MHC proteins. accessory molecules • T cells express a number of other invariant • • • molecules that serve diverse functions (coreceptor): CD4 (50-60%) : bind to MHC class II molecules (APC) CD8 (40%): bind to MHC class I molecules (APC) In healthy individual : CD4/CD8 =2/1 • CD4+ helper T cells: recognize antigens with class • • II MHC molecules CD8+ cytotoxic T cells: recognize Ags MHC class I molecules Both CD4 & CD8 are required to initiate signals that activate T cells that recognize antigens. T Lymphocytes • • • • CD 4+ T cells= T helper: secrete cytokines, help B cells to produce Ab, help macrophages to destroy microbes. The central role of CD4+ helper cells in immunity: is highlighted by the severe compromise that results from the destruction of this subset by (HIV) infection. CD 8+ T cells= cytotoxic TC: direct killing of virus-infected or tumor cells. NKT cells: small subset of T cells, expresses markers of NK and T cells. NK-T cells express limited diversity of TCRs, recognize microbial glycolipids but functions of NK-T cells are also not well defined. γ δ T cells • A small population of mature T cells, expresses TCR • • • composed of γ and δ polypeptide chains, do not express CD4 or CD8 molecules. γ δ TCR recognizes peptides, lipids, and small molecules, without a requirement for display by MHC proteins. γ δ T cells tend to aggregate at epithelial surfaces, of skin and mucosa of GI and urogenital tracts, protect against microbes that enter through epithelia. NKT cells and γ δ T cells: innate immunity cells Other proteins on T cells (CD28) • Other important invariant proteins on T cells include CD28 • functions as the receptor for molecules that are induced on APCs by microbes (costimulators), and various adhesion molecules • that strengthen the bond between the T cells and APCs and control the migration of the T cells to different tissues Signaling • T cells need two signals for • • • • • activation: Signal 1 : when TCR (CD4 and CD8) bind to MHC-bound antigen Signal 2: interaction of the CD28 molecule on T cells with the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) expressed on APCs. The importance of costimulation: In absence of signal 2, T cells fail to respond, T cells undergo apoptosis, or become unreactive . Activation T cells by antigen and costimulators, cause secretion of cytokines (IL2), T cells proliferate, generating a large number of antigenspecific lymphocytes. Do T cells detect free or circulating Antigens ? •(>95%) of T cells recognize only peptide fragments of protein antigens that are displayed on other cells bound to proteins of MHC (major histocompatibility complex) or in humans, human leukocyte antigen [HLA] complex). • MHC molecules function: display peptides for recognition by T lymphocytes. •Important point: •MHC restriction : T cells recognize only peptides displayed by that individual's MHC molecules. Extra slide for your information CAR T Cell therapy of Cancer Chimeric antigen receptors (CARs) chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors): The receptor proteins that have been engineered to give T cells the new ability to target a specific protein. The receptors are chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor. The evolution of CAR therapy: is an application of basic research to the clinic. CAR T cell Therapy 1. T-cells are removed from the patient's blood. 2. Then in a lab setting the gene that encodes for the specific antigen receptors are incorporated into the T-cells. 3. Thus producing the CAR receptors on the surface of the cells. 4. The newly modified T-cells are then further harvested and grown in the lab. 5. After a certain time period, the engineered T-cells are infused back into the patient. Major Histocompatibility Molecules (MHC) or HLA (Human Leukocye Antigen) • Importance of MHC: MHC molecules are fundamental to T cell recognition of Ags, genetic variations in MHC molecules are associated with immunologic diseases. •based on chemical structure, tissue distribution, and function, the MHC gene products are classified into three categories. Class I (HLA-A, HLA-B, HLA-C) encode cell surface glycoproteins involved in antigen presentation (all nucleated cells ) class II genes (HLA-D) cell surface glycoproteins involved in antigen presentation APC (DCs) Class III genes encode components of the complement system • The HLA complex and the structure of HLA molecules. • A) The location of genes (locus) in the HLA complex. • B) Schematic diagrams and crystal structures of class I and class II HLA molecules. Class I MHC molecules •Expressed on all nucleated cells and platelets. •encoded by three loci, HLA-A, HLA-B, and HLA-C • Each molecules: heterodimer, consisting of a α or heavy chain (44- kD) linked noncovalently to a light (12-kD) non polymorphic peptide called β 2M icroglobulin. •The extracellular region of the heavy chain is divided into three domains: α1, α2, α3 •bind to peptides derived from proteins synthesized within the cell (e.g., viral antigens). •CD8+ cytotoxic T cells: • recognize viruses •CD8+ T cells Class II MHC molecules • APC (DCs, macrophages, B cells), on endothelial cells and fibroblasts . • HLA-D: HLA-DP, HLA-DQ, and HLA-DR. • class II molecules present exogenous antigens (extracellular microbes, soluble proteins). • CD4+ : recognize extracellular pathogens •Antigen processing and recognition. •The sequence of events in the processing of a cytoplasmic protein antigen and its display by class I MHC molecules. •The recognition of MHC-displayed peptide by a CD8+ T cell. • Antigen processing and display by (MHC) molecules. A, In the class I MHC pathway, peptides are produced from proteins in the cytosol and transported to the endoplasmic reticulum (ER), where they bind to class I MHC molecules. The peptideMHC complexes are transported to the cell surface and displayed for recognition by CD8+ T cells. B, In the class II MHC pathway, proteins are ingested into vesicles and degraded into peptides, which bind to class II MHC molecules being transported in the same vesicles. The class II–peptide complexes are expressed on the cell surface and recognized by CD4+ T cells. HLA and Disease Association Many autoimmune diseases are associated with particular HLA alleles. The diseases that show association with the HLA locus are in three groups: 1. Inflammatory diseases •ankylosing spondylitis •several post infectious arthropathies •associated with HLA-B27 2. Autoimmune diseases autoimmune endocrinopathies associated mainly with alleles at the DR 3. Inherited errors of metabolism 21-hydroxylase deficiency associated with HLA-BW47 HLA and Disease Association A variety of diseases have been found to be associated with certain HLA alleles. The best known is the association between ankylosing spondylitis and HLA-B27; individuals who inherit this allele have a 90-fold greater chance (relative risk) of developing the disease than those who are negative for HLA-B27. B cells development bone marrow population 10% - 20% peripheral lymphocyte present in LN, spleen, tonsils, extralymphatic organs (GI) B cells activated, Ab secreting cells (Plasma cell) secrete Ig as mediators of humoral immunity IgM, IgG, IgA (95%) IgE ,IgD ( less) IgM, IgD (Membrane-bound antibodies) present on the surface of all mature, naive B cells (Ag-binding component of the B-cell receptor complex) Structure of antibodies and the B-cell Ag receptor complement receptors •BCR complex: composed of membrane IgM or IgD •sinaling proteins Igα and Igβ ( like CD3 proteins of the TCR, not bind Ag but essential for signal transduction) • CD21 is a receptor for complement component that promotes B- cell activation. • CD21 is also receptor for the Epstein-Barr virus (EBV), EBV infects B cells. •B cells express several other non polymorphic molecules that are essential for B-cell function including; complement receptors, Fe receptors, and CD40 •No need to MHC Natural Killer Cells population 10% - 15% blood lymphocytes, do not express TCR or Ig Morphologiy larger than small lymphocytes, contain azurophilic granules (called large granular lymphocytes) function innate immune, the early line of defense against viral infections and tumors. kill them without previous sensitization (reduced MHC expression). NK cells also secrete cytokines (IFN-γ), which activates macrophages to destroy ingested microbes, thus NK cells provide early defense against intracellular microbial infections. Cell surface Markers CD16 ( Fc receptor for IgG known as ADCC) , CD56 Activating receptors ( NKG2D) stimulate NK cell killing by recognizing ill-defined molecules on target cells (viral products) inhibitory receptors (killer cell Ig-like receptors and , CD94 family of lectins (carbohydraterecognizing proteins) inhibit the activation of NK cells by recognition of selfclass I MHC molecules. Activating and inhibitory receptors of natural killer (NK) cells. A, Healthy cells express self– class I MHC molecules, which are recognized by inhibitory receptors, thus ensuring that NK cells do not attack normal cells. healthy cells may express ligands for activating receptors or may not express such ligands (as shown), but they do not activate NK cells because they engage the inhibitory receptors. B, In infected and stressed cells, class I MHC expression is reduced so that the inhibitory receptors are not engaged, and ligands for activating receptors are expressed. The result is that NK cells are activated and the infected cells are killed. Macrophages induction of cell-mediated MQ that have phagocytosed immunity microbes , process Ags and present peptide to T cells ( as APC) cell-mediated immunity delayed hypersensitivity Secretion of cytokines ( IFN) Control T cell, B cell, endothelial, fibroblast humoral immunity phagocytose microbes that opsonized (coated) by IgG or C3b. Dendritic Cells 1) interdigitating dendritic cells ( DC) the most important APC, initiating primary IR • located under epithelia ( Langerhance), the common site of entry of Ag. • DCs express many receptors for capturing and responding to microbes (and other antigens), including TLRs and mannose receptors. • express MHC class II molecules , costimulatory molecules( B7-1 and B7-2), present antigens to activating CD4+ T cells. 2) follicular DC (FDC) • Have receptors for the Fc tails of IgG and for complement proteins present in the • can trap antigen bound to antibodies or complement germinal centers of proteins. lymphoid follicles( •selecting the B cells that have the highest affinity for the spleen, LN) antigen, thus improving the quality of the humoral immune response. 3. plasmacytoid DCs similar plasma cells. These cells are present in the blood and lymphoid organs, and are major sources of the antiviral cytokine type I interferon, produced in response to many viruses. The morphology of dendritic cells (DC). •A, Morphology:Cultured dendritic cells showing the prominent surface projections. •B, The location of dendritic cells (Langerhans cells) in the epidermis (stained blue using an immunohistochemical method). The functions of dendritic cells (DC). The role of dendritic cells in capturing microbial antigens from epithelia and transporting them to regional lymph nodes. • Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of Cell-Associated Microbes •Cell-mediated immunity •Polysaccharides and lipids •Protein antigens •IgG, IgA, IgE • heavy-chain class (isotype) switching •Humoral Immunity: Activation of B lymphocytes and Elimination of Extracellular Microbes (in the circulation and mucosal lumens) Cytokines: (messenger molecules of Immune system) • Cytokines are Low MW polypeptide, secreted by immune cells (activated lymphocytes and macrophages), function as mediators of inflammation and immune responses. • secreted in response to external stimuli (microbial products, antigen recognition, and other cytokines). • Their secretion typically is transient and is controlled by transcription and post-translational mechanisms. • Action of cytokines 1. autocrine (on the same producing cell ) 2. paracrine (on adjacent cells) 3. endocrine (at a distance from the site of production, uncommon). actions of cytokines: • The effects of cytokines tend to be: • pleiotropic (one cytokine can have diverse biologic • • activities, often on many cell types) redundant (multiple cytokines may have the same activity) Molecularly defined cytokines are called interleukins, referring to their ability to mediate communications between leukocytes. Cytokine classification based on their biologic activities and functions 1.Cytokines that mediate innate immunity & inflammation, the earliest host response to microbes and dead cells ( by activated macrophages , DCs, endothelial cells, lymphocytes, mast cells, and other cell types) The major cytokines in this group are: TNF, IL-1, and chemokines. IL-12, IFN-γ, IL-6, IL-23, and several other cytokines also participate in the early innate immune response. 2.Cytokines regulate lymphocyte growth, activation, and differentiation (adaptive immunity). By CD4+ helper T lymphocytes •proliferation and differentiation of lymphocytes ( IL-2 and IL-4) • activation of various effector cells (IFN-γ activates macrophages, and IL-5 activates eosinophils) 3. Cytokines that stimulate hematopoiesis.(colony- • increase output of leukocytes from the bone marrow , replace leukocytes consumed during immune and inflammatory reactions. •stimulate the growth new blood cells by acting on hematopoietic progenitor cells. stim ulating factors.CSF) Target cells ⸀⸀ Defining cytokines i, • ;.. •• ·j· IFN-� /' ' ' ·�·-ⴀⴀ " T, t Host defense ... 11tracellular ; palh㨀㸀;cns , ) Role In disea猀攀 䄀尀utcimmuni�䨀㨀 Chronic inHamma tion Macrophages . .,"' .. t .⸀娀 -• - IL-4 IL-5 IL-13 IL- t 7 IL-22 ⴀ娀��-㨀㨀!;• E�sincph椀氀s , · · -··Ⰰ椀 . . 堀嬀 -'•··,. ! '. ' ·· !: . ....-" Nculrop�ils '•, Helmi n1hs Allergy E㸀㨀tracel�1lar pa琀氀,漀ꌀens Autoi mmun it�, :·' Fig ,S. IO Subse挀猀 of he per T (T":, ,e氀氀s. In res瀀挀rse to s tl m琀氀i {mai n ly cycoklr䔀椀S) p1 ·&s⸀䔀,nc ac dl� 挀椀m& of ancl �n reco�n don, mil\•e CD41 T .: e氀氀s may dif. ferentiate i nto p opul ations of effe-�•:o r ce氀氀s that prodtKe disti nct 猀⸀ets of 挀㄀:oki n€ s �hat an c·n d i f fe rent ce氀氀s ⠀椀n di挀愀te d as tar☀攀t c.e 氀氀 s} an d m€d iate di f feren: fur ctions. The r漀氀es of �h ese Ⰰ㬀u bse琀猀 in hon defeme ar d i爀渀mJnologic