CELLULAR BASIS OF IMMUNE RESPONSE Learning objectives • By the end of the lecture, the student should be able to know: • Cell- mediated immune response • Different types of T cells and their functions • Antigen processing and presentation • Method of activation of Tcells • Method of activation of macrophages and delayed type hypersensitivity • MHC, different classes, structure, expression and gene defects Cell-Mediated Immunity • An adaptive immune response mediated by specific cells of the immune system Primarily T lymphocytes (T cells), but also macrophages and NK cells. Formally defined as immunity that can be transferred from one organism to another by lymphoid cells, but not by serum antibody. • T cells are the main agents of cellular immunity Host defenses against extracellular infection are mediated by: - Antibody - Complement - Macrophages Intercellular infections are mediates by CMI CMI are responsible for: - Resistance to intracellular pathogens - Resistance to fungal and protozoal infections - Resistance to tumors
Transcript
CELLULAR BASIS OF IMMUNE RESPONSE
Learning objectives
• By the end of the lecture, the student should be able to know:
• Cell- mediated immune response
• Different types of T cells and their functions
• Antigen processing and presentation
• Method of activation of Tcells
• Method of activation of macrophages and delayed type hypersensitivity
• MHC, different classes, structure, expression and gene defects
Cell-Mediated Immunity• An adaptive immune response mediated by specific cells of the immune system
Primarily T lymphocytes (T cells), but also macrophages and NK cells.Formally defined as immunity that can be transferred from one organism to another by lymphoid cells, but not by serum antibody.
• T cells are the main agents of cellular immunityHost defenses against extracellular infection are mediated by: - Antibody- Complement- Macrophages
Intercellular infections are mediates by CMI
CMI are responsible for: - Resistance to intracellular pathogens - Resistance to fungal and protozoal infections - Resistance to tumors
T cells continuously circulate via the blood and lymph through different lymph nodes until the either find presented antigen or eventually die
When a T cell encounters an APC displaying antigen to which it can bind, it stops migrating and binds strongly to the APC.
Within about 2 days (48 hours), most antigen-specific T cells have been trapped by antigen and within about 4 to5 days armed effector T cells are migrating out of the lymph node.
CMI may play a role in some harmful conditions:
- Hypersensitivity reactions type IV (contact dermatitis)
Functions of the different T cell types• CD8+ cells:
Kill virally infected cells• CD4+ cells:
TH1: Activate macrophages to aggressively ingest antigen and to kill ingested microbes.TH2: Stimulate B cells to differentiate into antibody-producing plasma cells. B cells will only undergo isotype switching after receiving T cell help. The Ig class that a B cell switches to is specified by the types and balance of cytokines secreted by the helper T cell. Most plasma cells migrate to the bone marrow where they live out the rest of their lives.
The T cell Receptor• Similar in structure
to Immunoglobulins (similar to a single Fab fragment.• Composed of two glycoprotein chains (/ or /).
Most mature T cells have TCRs composed of an chain and a chain (they are called / T cells).
• Each chain has a constant region and a variable region, similar to an antibody light chain.
• A TCR recognizes a small(8-13 aa) peptide epitopedisplayed on MHC
Characters of CMI Macrophages present antigen via their surface MHC to T-cells
T-cells recognize antigen through their specific receptors (TCR)
A specific T-cell clone becomes activated and begins to proliferate
Activated TH lymphocytes becomes effectors cells that secrete cytokinesCytokines stimulate other effectors cells of CMI and humoral immune response and mediate the following:Attract monocytes, macrophages and lymphocytes to the site
- Activate macrophages to kill intracellular microbes- Promote activity of CD8 CTLs which directly kill virus infected cells, tumour cells, and graft
rejectionThey activate NK cells increasing their cytotoxic functions
- Stimulate B-cells to differentiate into plasma cells that secret antibodies
1) Antigen Processing and Presentationa- Extracellular proteins are internalized into vesicular compartment of APCs (Dentritic,
macrophages,B-cells)They are degraded to generate peptidesThese peptides bind into class II MHC molecules
Peptide-MHC II complex is transported to surface of APCs to be presented to CD4 TH cells (T Helper cell)
Outcome: Secretion of cytokines by TH cells
1) Antigen Processing and Presentation
b- Endogenously synthesized proteins are degraded to peptides (all nucleated cells e.g virus infected cells)
They bind to class I MHC in endoplasmic reticulum Peptide-MHC I complex is expressed on surface of nucleotide cells to be represented to CD8 cytotoxic cells
Outcome:Killing of presenting cells by CTLs
2) Activation of T-cells Mature CD4 and CD8 cells are activated by two signals: First signal is recognition of antigenic peptide-MHC complex on surface of APC by TCR-
CD3 complex CD4 and CD8 molecules are co-receptors that stabilize the interaction of TH cells and
TC-cells respectively with APCs CD3,CD4, and CD8 act as signal transduction molecules
Second co-stimulatory signal is: interaction of CD28 on T-cells with CD7 on APCs
2) Activation of T-cells TH-cells express IL-2 receptors and secrete cytokines including IL-2 IL-2 auto activate TH-cells APC release IL-I which acts on both APC and TH cell to promote their activation All mentioned interactions lead to activation of mature TH-cells Mature TH-cells proliferate and differentiate into effectors antigen specific TH-cells
releasing cytokines Some of them become memory cells which provide secondary immune response Cytokine released from activated TH-cells activate macrophages, NK and B-cells
3) Activation of Macrophages and Delayed Type Hypersensitivity (DTH) Activated TH cells (TH1) secrete IFN-γ which activates macrophages and increase their
ability to kill ingested intracellular pathogens
The process of activation of macrophages, NK cell and cytotoxic T-cells, infiltration and proliferation of inflammatory cells, stimulated by cytokines released from TH-cells (TH1) is important protective mechanism against intracellular pathogen
3) Activation of Macrophages and Delayed Type Hypersensitivity (DTH) Activated macrophages can also kill abnormal host cells (abnormal or tumor cells) Its cytotoxicity is non specific and stimulated by TNF, nitric oxid, enzymes and oxygen
metabolites
If infection is not fully resolved, activated macrophages cause tissue injury and fibrosis i.e. DTH reaction
MHC• Group of genes that code for proteins found on the surfaces of cells that help the immune
system recognize foreign substances. • MHC proteins are found in all higher vertebrates. • In human beings the complex is also called the human leukocyte antigen (HLA) system.
MHC Class I structure• Comprised of two polypeptide chains; the chain and the invariant chain, called 2-
microglobulin• Four domains, three formed from the MHC-encoded chain & the 2-• The 1 and 2 domains form the peptide binding site
Expression of MHC class I/II on different cell types• MHC class I molecules present peptides from pathogens, commonly viruses, to CD8
cytotoxic T cells• Viruses can infect any nucleated cell
• MHC class II proteins present peptide to CD4+ T cells.• CD4+ T cells recognize MHC Class II and activate other effector cells of the immune
system.
Conclusion Class I and II• The class I and II MHC genes encode human leukocyte antigens (HLAs), proteins that are
displayed on the cell surface and define an individual’s tissue type .
• There are many possible tissue types in the population because each HLA exists as a large number of varieties.
• Everyone's immune system is tolerant of its own HLAs, but if foreign HLAs are detected then the cells displaying them are attacked and destroyed (body rejects grafts and transplants from donors that have not been matched for tissue type).
• The class I and II MHC proteins also perform the important function of antigen presentation. This is how the immune system finds out what is happening inside our cells even though it can only survey them from the outside.
• Proteins inside the cell are broken into short fragments and displayed as peptide antigens by MHC proteins on the surface. This helps the immune system to discriminate between normal (self) antigens and those that are foreign and potentially dangerous.
Class III• Class III encode several components of the complement system, a collection of soluble proteins found in the blood that targets foreign cells and breaks open their membranes. • Adjacent to the class III region is a group of genes that control inflammation. • Further genes with various immune and non-immune functions are dotted throughout the complex.
MHC Genes DefectsDefects in certain MHC genes lead to autoimmune disorders in which the body fails to recognize self-antigens. Ex. multiple sclerosis, some forms of arthritis and diabetes, and inflammatory bowel disease.
