Effector functions of immune system

Effector response-cell mediated and antibody mediated

1. Effector Responses Abisha.S.J

2. The theory states that in a pre-existing group of lymphocytes ( specifically B cells ), a specific antigen only activates (i.e. selection) its counter-specific cell so that particular cell is induced to multiply (producing its clones ) for antibody production. This activation occurs in secondary lymphoid organs such as the  spleen and the lymph nodes Clonal selection theory

3. 1) A  hematopoietic stem cell  undergoes differentiation and genetic rearrangement to produce 2) immature lymphocytes with many different antigen receptors. Those that bind to 3) antigens from the body's own tissues are destroyed, while the rest mature into 4 ) inactive lymphocytes . Most of these will never encounter a matching 5) foreign antigen , but those that do are activated and produce 6) many clones of themselves. Clonal selection of lymphocytes

4. Two types of cells are produced by clonal selection Effector cells and  Memory cells. Effector cells are the relatively short-lived activated cells that defend the body in an immune response. Effector B cells are called plasma cells and secrete antibodies, and Activated T cells include cytotoxic T cells and helper T cells , which carry out cell-mediated responses. Effector cells The production of effector cells in response to first-time exposure to an antigen is called the primary immune response.

5. Memory cells also are produced at this time, but they do not become active at this poin t. If the organism is reexposed to the same antigen that stimulated their formation, the body mounts a second immune response that is led by these long-lasting memory cells, which then give rise to another population of identical effector and memory cells. . This secondary mechanism is known as immunological memory

6. The effector functions of the immune system have both humoral (antibody) and cellular arms . Both co-operate to clear the body of infection and, in some cases

7. Effector functions Antibody mediated Cell mediated

8. Clonal selection of a B cell The effector molecules of the humoral branch are antibodies , the secreted version of the highly specific receptor on the surface of B cells.

9. The humoral arm of the immune system refers to the activities of antibodies secreted by B lymphocytes. The antigen specificity, isotype , and interactions with FcRs are all important features of antibody effector function. Antibody-binding receptors, which bind to the constant regions of antibodies and are therefore called Fc receptors or FcRs , determine which cells an antibody can recruit to aid in its destructive mission

10. Antibodies Mediate Effector response Antibodies inhibit and clear infection By blocking the ability of pathogens to infect (neutralization ),

11. By coating pathogens so that they are recognized and phagocytosed by innate immune cells ( opsonization ), By recruiting complement to the pathogen ( complement fixation ), and

12. By directing other cells of the innate immune system to kill infected cells ( antibody-dependent cell cytotoxicity ). Antibody-dependent Cell Cytotoxicity

13. Antibody effector functions

14. Each antibody isotype has different effector functions: IgM and some IgG antibodies fix complement IgG antibodies mediate ADCC IgE antibodies induce release of inflammatory molecules from granulocytes to kill parasites IgA antibodies are a major isotype in bodily secretions and block entry of bacteria and toxins to the bloodstream. Antibody isotype

15. Phagocytosis of antibody antigen complexes by macrophages Fc receptors Fc receptors are responsible for many of the effector functions of antibodies.

16. Transcytosis of antibodies through epithelial cell layers PolyIg receptors ( PolyIgR ) expressed by the inner surface of epithelial cells will bind dimers and multimers of IgA and IgM antibodies and transfer them through the cell to their apical (outer) surface and into the lumen of an organ (e.g., the GI tract). This is a process referred to as transcytosis and is responsible for the accumulation of antibodies in bodily secretions.

17. Lysis of antibody bound infected cells by NK cells (ADCC); protecting serum antibodies from degradation . regulating the activities of innate immune cells.

18. FcRs are expressed by many cell types in the body and generate signals when bound to antibody-antigen complexes . FcR generated signals can either activate or inhibit the activity of cells. Whether an FcR is activating or inhibiting depends on whether it includes or associates with an ITAM ( activating ) or an ITIM (inhibiting) protein motif Immunoreceptor tyrosine-based inhibition motif (ITIM) immuno-receptortyrosine activation motif (ITAM). Conserved sequence of amino acids that is found in the  cytoplasmic  tails of many  receptors of the immune system

19. Most FcRs are activating receptors and are associated with signaling proteins that contain the Immuno-receptorTyrosine Activation Motif (ITAM) . Fc γ RIIB is an inhibiting FcR and includes an Immunoreceptor Tyrosine Inhibition Motif (ITIM) in its intracellular region Antibody-binding polypeptides – blue Accessory signal- transducing polypeptides- green.

20. The effector cells of the cell-mediated immune system include cells of the innate immune system ( natural killer [NK] cells) cells of the adaptive immune system Helper CD4T cells (TH cells) and CD8 cytotoxic T lymphocytes (CTLs or TC cells). . Cell mediated effector response NKT cells are also participants and have features of both the innate and adaptive immune systems

21. Cellmediated immunity consists of both helper T cells ( CD4 TH) and several types of cytotoxic cells. Stimulation of immune response by activated helper T cells

22. Effector cytotoxic cells arise from both the adaptive and innate immune systems and, therefore, include both antigen-specific and -nonspecific cells Antigen non- specifi c (innate immune) cells that contribute to the clearance of infected cells include NK cells and non lymphoid cell types such as macrophages, neutrophils , and eosinophils Antigen-specific cytotoxic cells include CD8 T lymphocytes (CTLs or TC cells), as well as the CD4 NKT cell subpopulation Populations of cytotoxic CD4 TH cells may contribute to delayed-type hypersensitivity.

23. Naïve TC cells are incapable of killing target cells ( also referred to as CTL precursors (CTL-Ps) to denote their functionally immature state. Only after a CTL-P has been activated does the cell differentiate into a functional CTL with cytotoxic activity. Cells of the adaptive immune system

24. In order to become functional CTLs , naïve TC precursors (CTL-Ps) must engage with APCs that have been previously activated (licensed). CD4 T-cell help is not necessary for this first activation step, but is required for optimal generation of memory and proliferation of CTLs. This involves 3 signalling steps .

25. An antigen-specific signal transmitted by the TCR complex upon recognition of a class I MHC-peptide complex on a “licensed” APC.

26. A costimulatory signal transmitted by the CD28-CD80/86 (B7) interaction of the CTL-P and the licensed APC A signal induced by the interaction of IL-2 with the high-affinity IL-2 receptor, resulting in proliferation and differentiation of the antigen-activated CTL-P into effector CTLs IL-2 can be generated by helper T cells as well as by the CD8 T cell itself.

27. Antigen-specific effector T cell populations can be identified and tracked by labeling with MHC tetramers MHC tetramers A homogeneous population of peptide-bound class I MHC molecules is conjugated to biotin and mixed with fluorescently labeled streptavidin In the ideal situation , four biotinylated MHC-peptide complexes bind to the high-affinity binding sites of fluorescent streptavidin to form a tetramer . .

28. Addition of the now fluorescent tetramer to a population of T cells results in binding of the fluorescent tetramer only to those CD8 T cells with TCRs that are specific for the peptide-MHC complexes of the tetramer

29. CTLs induce cell death via the following mechanisms: Directional release of granule contents Granzyme and perforin mediated cytolysis The fas-fasl pathway. Both trigger apoptosis in the target cells

30. Directional release of granule contents

31. The perforin -mediated cytotoxic response of CTLs involves several steps: TCR-MHC mediated recognition of target cells Formation of CTL/target-cell conjugates and immune synapse formation Repositioning of CTL cytoplasmic granules toward the target cell Granule release Formation of pores in the target-cell membrane Dissociation of the CTL from the target Death of the target cell Granzyme and perforin mediated cytolysis Fas -mediated killing also involves conjugate and immune synapse formation where Fas-FasL interactions occur.

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33. Other non antigen-specific cells of the innate immune system ( NK cells and granulocytes ) can also kill target cells via antibody-dependent cell-mediated cytotoxicity (ADCC), resulting in the release of lytic enzymes, perforin , or TNF that damage the target-cell membrane. NK cells induce apoptosis of tumor cells and virus infected cells by mechanisms similar to CTLs ( perforin induced pore formation, as well as Fas-FasL interactions), but are regulated by distinct receptors. cells of the innate immune system

34. How NK cells distinguish self from non (or altered) self. It was proposed that NK cells kill when they do not perceive the presence of normal self-proteins on a cell, the missing self model Missing self model. NK cells kill those cells that have lost or reduced their levels of MHC class I, a ubiquitously expressed self protein— a phenomenon described by the missing self model.

35. Model of how cytotoxic activity of NK cells is restricted to altered self cells An activating receptor on NK cells interacts with its ligand on normal and altered self cells, inducing an activation signal that results in killing.

36. Engagement of inhibitory nk -cell receptors such as inhibitory kirs and CD94-NKG2 by class I MHC molecules delivers an inhibition signal that counteracts the activation signal. NK cell killing is regulated by a balance between positive signals generated by the engagement of activating NK receptors and negative signals from inhibitory NK receptors

37. NK-cell receptors fall into two major structural groups based on their extracellular regions: the lectin -like receptors and the Ig -like receptors. Whether receptors are activating or inhibiting depends on their intracellular regions: ITAM expressing receptors are activating, ITIM expressing receptors are inhibiting. Nk cell receptor

38. NKT cells have characteristics common to both T lymphocytes and NK cells NKT cells do not form memory cells. most express an invariant TCR and markers common to NK cells. They exhibit both helper and cytotoxic activity and kill cells predominantly via FasL-Fas interactions . NKT cells

39. Immune cell cytotoxicity can be measured in vitro by Mixed lymphocyte reaction (MLR), or Cell-mediated lympholysis (CML) via radioactivity or fluorescence. They can be assessed in vivo by Graft versus host (GVH) responses Increases in spleen size ( splenomegaly ). Experimental assessment of Cell mediated cytotoxicity

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