Lecture 3: T Cells, MHC and Lymphocyte Activation Flashcards
T Cell Receptors
T cells do not recognize native antigen. The antigen must be proceesd by the APC and recognized in conjunction with a MHC molecule
T cells are heterodimers of mostly alpha and beta chains
Each apha chain has an antigen binding site, a variable region, a constant region, and a transmembrane region
Develops in thymic cells by somatic rearangments of TCR v, D, and J gene segments
Requires RAG 1 and RAG2 enzymes
TC
Cytotoxic T cells
CD8 is the co-receptor that also binds MHC class 1
The TCR recognizes the MHC plus the peptide of the antigen on the antigen presenting cell
TC cells recognize and kill virus infected cell by releasing perforin which forms channels in the membrane or by releaseing Fas on the target cell and activating the death pathway
Viral proteins are made endogenously
TH
T helper cells
CD4 Co-receptor binds MHC Class II
Recognize exogenous peptides presented in association with MHC class II molecules of APCs
Interaction between T cells and antigen presenting cells that leads to T cell activation
Since T cells do not recognize native antibody, the native antigen protein is denatured by the antigen presenting cell and the antigen peptide complexes with the MHC molecule
Forms the tripeptide complex: T cell receptor, peptide antigen, and MHC molecule
- Cut - bacteria enters the body
- Antigen is taken to the lymph node in the context of an MHC receptor
- The T cell recognizes the peptide antigen in the context of a MHC molecule
- T cell is activated
MHC Class I Molecules
Expressed on nearly all nucleated cells (except RBCs, sperm, and ovum)
Recognized by TC cells - CD8+
TC cells recognize and kill virus infected cells - recognize the endogenous viral peptide presented in the context of MHC class 1
Intracellular antigen
MHC Class II Molecules
Expressed only on antigen presenting cells (APC) - Dendritic cells, macrophages, and B cells
Recognized by TH cells - CD4+
TH cells recognize exogenous proteins presented in association with MHC class II molecule of antigen presenting cells
T cell Education
TCR genes rearrange in the thymus
T Cells are educated to determin self antigens in the thymus
The thymus activates a gene that produces self epitopes, and if T cells bind, they are destroyed to prevent autoimmunity from developing
Positive Selection
T cells undergo positive selection in the thymus to select for T cells that recognize antigen in the context of MHC receptors
Negative Selection
T cells undergo negative selection in the thymus to eliminate T cells that react with self peptides
Gets rid of self reactive t cells due to a gene in the thymus producing self epitopes om the thymus during dedevelopment. When self reactive t cells react with the epitope, the t cells are are deleted
Prevents autoimmunity from developing
Antigens recognized by B Cell Receptors
B cell receptors recognize native antigen
Antigens recognized by T Cell Receptors
T cell receptors recognize peptide from the antigen in the context of a MHC molecule
How is an immune response initiated?
- Antigen is collected in the lymphatics and transported tot he draining lymph node by APC (dendritic cells)
- In the lymph node the activated dendritic cells (APC’s) interact with, and stimulate TH cells
- TH cells interact with, and activate antigen specific B cells
- B cells then form germinal centers and undergo germinal center reactions (isotype switch, somatic hypermutation, diffenetiation of B cells to plasma cells, and generation of memoory B-cells)
How does viral immunity develop?
- The host cell proteosome degrades viral proteins which are transported to the ER
- Peptides bind to MHC class I molecules and transport through the golgi apperatus
- MHC class I presents peptides at the cell surface and activates CD8 Tc Cells
- Activated Tc cells can kill the virus infected cell through a perforin dependent killing or through a fas dependent killing mechanism
How does immunity to extracellular pathogens develop?
- The cell engulfs the extracellular antigen in an endocytic vesicle
- Peptide is produced in a phagolysosome
- The peptide binds MHC class II molecules through vessicle fussion
- The MHC class II presents the peptiide at the cell surface and activates CD4+ Th cells
- Activated Th cells can then differentiate and prolliferate and effector Th cells will develop in response to specific cytokines released
TH Cell Activation
Costimulation (2 signals) is required for activation of TH cells
- TCR recognition of the peptide in the context of MHC receptor on an APC (often dendritic cell)
- Interaction of CD28 on T cells and B7 on APC (costimulatory molecules)
Activation of Th cells causes the release of a specific set of cytokines that stimulate proliferation and differentiation into effector T cells
TH1
Activates macrophages to kill intracellular pathogens and activate cytotoxic T cells to kill virus infected cells
The antigen presenting cell releases IL12 and IFNy
The activated T cell then releases IL2 and IFNy to differentiate into Th1 cells
TH2
TH2 cells help activate B cells, which are activated to differentiate into plasma cells and secrete antibody which protects the host from extracellular pathogens
Activation and differentiation of B cells occurs in the lymph nodes and germinal centers
IL-4 promotes TH2 activation
TH17
Promotes the release of IL-17 and induces a neutraphill response
Early in the immune response
TH2 cells are activated by IL-6 and TGFbeta
TReg
CD4+ T cells that supress T cell activity and help prevent autoimmunity
Develop in resonse to TGFbeta
What is the importance of cytokines in the immune response?
Cytokines produced by the dendritic cell activae a T cell to release another set of cytokines that influence the proliferation and differentiation of a specific subset of Th cells
3 Major effector mechanisms of the immune system
- Antibody and complement can together kill extracellular bacteria
- CD8+ CTL kills virus infected cells
- Activated macrophages results in delayed hypersensitivity and kills intracellular organisms
Effector T Cells
CD4+
- TH1
- TH2
- TH17
- T Reg
CD8+
- CTL (cytotoxic t lymphocytes)
Memory
Lymphocytes generated following enncounters with antigen that are charachteristically long lived
They are more readily stimulated than naive lymphocytes and mediate a secondary response to subsequent encounters with antigen
Specificity
The capacity of an antibofy and T cell recptor to recognize and interact with a signle unique antigenic determinant or epitope
Cytokines
Small secreted proteins that regulate the intensity and duration of the immune response by wxerting a variety of effects on lymphocytes and other immune cells
APC
Any cell that can orocess and present antigenic peptides in the context of a MHC class 2 molecule and deliver a costimulatory signal necessary for T cell activation
Dendritic cells, B Cells, Macrophages
BCR
A complex comprised of a membrane bound immunoglobulin molecule
TCR
Antigen binding molecule expressed on the surface of T cells
Recognizes antigen in the context of a MHC molecule
Memory B Cells
An antigen committed persistent B cell
B cell differentiation can result in the formation of plasma cells and memory cells which are involved in the secondary response
Primary immune response
Immune response after an initial exposure to antigens. Characterized by short duration and low magnitude of response when compared to subsequent exposure response
Secondary Immune Response
The immune response following exposure to previously encountered antigens.
The secondary response is more rapid and is greater in maggnitude and durration
Humoral Immunity
Host defenses that are mediated by antibody present in the plasma, lymph, and tissue fluids. (B cell - plasma cell)
It protects agains extracellular bacteria and foreign molecules
Transfer of antibodies confers theis type of immunity on the recipent
Cellular Immunity
Host defenses that are by antigen specific T cells and various nonspecific cells of the immune system
Protects against intracellular bacteria, viruses, and cancer cells
Is responsible for graft rejection
Transfer of primed T cells confers this type of immunity on the recipient
Co-Receptor
CD4+ - T Helper Cells
CD8+ - Cytotoxic T Cells
Costimulatory Molecule
Additional signal that is required to induce prolifferation of antigen-primed T cellsand is generated by the interaction of CD28 on T cells with B7 on antigen presenting cells
What is the risk of developing a large T cell repertoire?
Self reactive T cells can develop, resulting in autoimmunity
To get rid of self reactive T cells, there is a gene in the thymus that produces self epitopes. If the T cells bind to the self epitopes during development, the self reacting T cells are deleted
What occurs in Germinal Centers?
- B cells can differentiate to form plasma cells which secrete antibody
- B cells can become memory B cells which circulate looking for antigen
- B cells undergo somatic hypermutation which can only occur in the germinal center, and selection for high affinity antibodies occurs
How does the immune system respond to a protein antigen?
- The system is exposed to an antigen at a distant site
- The dendritic cell takes up the antigen and transports it to the draining lymph node via the lymphatics
- A naïve CD4+ cell recognizes an antigen in the context of a MHC molecule on an APC
- The activated T cell develops into a specific type of T cell based on a specific cytokines (dendritic cells are thought to stimulate the release of a certain set of cytokines to direct Th development based on the antigen)
- The activiated Th cells release a different set of cytokines which have different functions based on the type of T cell
- Th1 – releases cytokines that activate macrophages to kill intracellular bacteria
- Th2 – releases cytokines that activate B cell differentiation
- Th17 – release cytokines that activate the recruitment of neutrophils to the site of infection resulting in an inflammatory response
- T reg – release cytokines that inhibit CD4 T cells
- The activated B cells form germinal centers and undergo germinal center reactions
