L13: Cell Mediated Immunity Flashcards
What does the fate of antigens in vivo and the type of immune response that develops depend on?
- Nature of antigen
- Route of antigen entry
- Immunological status of individual
What is the purpose of cell-mediated immunity?
Defense mechanisms against microbes that survive within phagocytes or infect non-phagocytic cells
What cells is CMI mediated by?
- Mediated by cells of the innate immune system (T cell independent): phagocytosis, natural killer cells, cytokines, complement
- T cell mediated: initiated by T cell recognition of MHC-bound peptide antigens expressed on the surface of cells infected w/ viruses and intracellular bacteria
What are sequential events in the progression of the immune response?
- Antigen capture and presentation
- Recognition of antigen by T and B cells
- Clonal expansion and differentiation of antigen-activated lymphocytes
- Migration of effector cells and molecules to sites of antigen in tissues
What are T cell independent CMI responses?
Phagocytosis
NK cell cytotoxicity
Cytokines (e.g. TNF: IL-12)
Complement
What is the CMI response to phagocytized microbes?
Response is mediated by T cells that recognize microbial antigens, and produce cytokines, such as IFN-γ and TNF, that enhance the ability of phagocytes to kill the microbes and stimulate inflammation
Antigen-specific CD4+ Th1 cells recognize antigenic peptide-MHC II complex and produce phagocyte-reactivating IFN-γ
Antigen-specific CD8+ recognize antigenic peptide-MHC I complex and also produce IFN-γ
Antigen-activated T cells also produce cytokines, such as TNF and lymphotoxin (LT) that stimulate inflammation
What is the downside to CMI response to phagocytized microbes?
Tissue injury due to delayed type hypersensitivity (DTH) reaction may occur
What is the response to microbes that infect and replication in various cell types mediated by?
CD8+ cytotoxic T lymphocytes (CTLs) that kill infected cells and eliminate the reservoirs of infectious organisms
CTLs are the principal defense mechanism against viruses that replicated in the cytoplasm of infected cells
CTL killing is also a mechanism to eliminate microbes taken up by phagocytes, but exist in the cytosol outside of the phagosomes
What is the response to helminthic parasites mediated by?
TH2 cells which stimulate IgE antibody production and activate eosinophils that bind and destroy IgE coated helminths
Describe the induction phase of CMI
Antigen recognition in lymphoid organs → T cell expansion and differentiation → differentiated effector T cells enter circulation
Describe the effector phase of CMI
Differentiated effector T cells enter circulation → effector T cells encounter antigens in peripheral tissues → effector T cells encounter antigens in peripheral tissues → secrete their products (such as TNF and IFN-γ) locally
What are the subsets of T helper cells?
Th1
Th2
Treg
Th17
What is/are the prototypic cytokine(s) produced by Th1? What is the primary function of these?
IFN-γ
Macrophage activating factor
What is/are the prototypic cytokine(s) produced by Th2? What is the primary function of these?
IL-4, IL-5, IL-13 (and IL-10)
Function in switch factor (in isotype switching)
IL-4 in particular is the switch factor for IgE
Describe the development of Th1 subset
Th1 differentiation pathway is the response to microbes that infect or activate macrophages and NK cells
IL-12 production during the initiation of response factors Th1 cell differentiation →
IL-12 binds to receptors on antigen-stimulated CD4+ T cells and activates the transcription factor STAT4, which promotes Th1 differentiation →
another transcription factor, T-bet, provides an amplificaiton mechanism for Th1 differentiation →
IFN-γ is the signature cytokine produced by Th1 differentiation
What stimulates IL-12 gene transcription and production in APC?
APC has receptor for IFN-γ which when activated stimulates IL-12 production
CD40:CD40L engagement by a T helper cell drives IL-12 production
What are the effector functions of Th1 cells?
General rule is that if Th1 cells are involved, think CMI responses
IFN-γ stimulates macrophage activation (enhanced microbial killing)
IFN-γ also stimulates complement-binding and opsonizing by antibodies
IFN-γ also helps naive CD8 cells to engage antigen and differentiate to become cytolytic T cells
LT and TNF stimulates activation of neutrophils (enhanced microbial killing)
When macrophage is activated by Th1 cells, what does this cause?
Activated macrophage has:
Increased expression of costimulators (B7 molecules) → Increased T cell activation (amplification)
Secretion of cytokines (TNF, IL-1, IL-12) → increased leukocyte recruitment (inflammation), more Th1 differentiation, and IFN-γ production
Increased expression of MHC molecules → increased T cell activation (amplification)
Production of ROI and NO → killing of microbes in phagolysosomes (effector function of macrophages)
Describe the development of Th2 subset
Th2 differentiation pathway is the response to helminths and allergens, which cause chronic T cell stimulation
Th2 differentiation is dependent on IL-4, which functions by activating STAT6 transcription factor (IL-4 initially produced by antigen-activated naive CD4+ cells are though to trigger Th2 differentiation) → GATA-3, another transcription factor, provides an amplification mechanism for Th2 differentiation → IL-4, 5, 10, and 13 are the defining cytokines produced
What are the effector functions of Th2 cells?
General rule is that if Th2 cells are involved, think humoral immune responses
IL-4 → enhances production of IgG as well as IgE (involved in allergic reactions and parasitic infestations)
IL-5 → eosinophil promoting factor since in a parasitic infection, will need more eosinophils at site of infection
IL-10 and IL-4 → suppression of macrophage activation
Th1 - Th2 crosstalk
Production of IL-10, IL-4, IL-13 (anti-inflammatory cytokines) by Th2 inhibits macrophage activation
Production of IFN-γ by Th1 causes macrophage activation
Th1 cells won’t be involved in responses that are Th2 dominant and vice versa
Describe the development of Treg subset and its role
Produced in response to TGF-β and act to negatively regultae immune responses by production of cytokines (such as IL-10) that suppress immune function
Foxp3 transcription factor also involved
Treg cells are thought to inhibit development of autoimmune diseases
Describe the development of Th17 subset and its role
Arise when IL-6 is produced along w/ TGF-β, which occurs when APC are activated during an inflammatory response
RORγt transcription factor also involved
Production of Th17 appear important for immune protection against certain pathogens They produce pro-inflammatory cytokines (such as IL-6, IL-17, and others)
However, Th17 cells also promote development of autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis
What is the pathway of development of the 4 T cell subtypes dermined by?
Interaction b/w APC and antigen-specific T cells and cytokines that are being produced as a result of that interaction
Name the cytokines and transcription factors that drive the production of each of the T cell subtypes
Th1
Cytokine: IL-12
TFs: STAT4 & T-bet
Th2
Cytokine: IL-4
TFs: STAT6 & GATA-3
Treg
Cytokine: TGF-β
TF: Foxp3
Th17
Cytokine: TGF-β & IL-6
TF: RORyt
What are the cytotoxic effector cells?
CTLs
NKs
What are the different pathways of differentiation of CD8+ CTLs?
- Role of co-stimulation: CD8+ T cells recognize antigen + costimulators on professional APCs → CTL differentiation w/o helper T cells
- Role of TH cells via cytokine production: CD4+ helper T cells produce cytokines that stimulate CTL differentiation; this occurs when peptide antigen can be engaged, but there is no co-stimulation (such as in liver cells which don’t have that)
- Role of TH cells via CD40-CD40L interaction: CD4+ helper T cells enhance the ability of APCs to stimulate CTL differentiation; with a CD4+ cell that can engage CD40-CD40L, which causes upregulation of costimulatory molecules
Describe the steps in CTL-mediated lysis of target cells
Antigen recognition and conjugate formation (via MHC class I) → CTL activation → delivery of lethal hit (granules are exocytosed) → detachment of CTL → target cell death (granule components cause activation of caspases, leading to apoptosis)
OR
FasL-Fas mediated target cell apoptosis: FasL on CTL interacts w/ Fas on target cell → apoptosis of target cell
When do CTLs stop apoptosing?
When they run out of granules
NK cell mediated cytoxicity
Receptors are different, by killing mechanism is pretty much the same as CTL
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Antibody binds to surface antigen on a viral-infected cell → creates antibody-coated cell → Fc receptors on NK cells can bind via the Fc region of the antibody molecules → lysis of antibody-coated cell
This is not unique to NK cells
ADCC effector cells: NK cells, macrophages, eosinophils (these all have receptors for Fc portion of antibody molecules and can kill under certain conditions)
