Adaptive Immune Response Flashcards
Hematopoietic stem cells give rise to
Common myeloid progenitor and common lymphoid progenitor cells
Myeloid progenitors give rise to (4)
- Megakaryocytes- give rise to thrombocytes
- Erythrocytes
- Mast cells
- Myoblasts
Lymphoid progenitors give rise to (2)
- NK cells
- Small lymphocytes
Myoblasts give rise to (4)
- Basophil
- Neutrophil
- Eosinophil
- Monocyte- gives rise to macrophages
Small lymphocytes
Give rise to B and T cells. B cells can further differentiate into plasma cells
Sentinel cells
Include dendritic cells, macrophages, and NK cells. These cells constantly patrol all the tissues looking for signs of anything out of ordinary or of foreign origin. Information is relayed to the “headquarters” which are the lymph nodes
NK cells
NK cells distinguish normal, healthy target cells by a
two-receptor mechanism (MHC I and viral protein)- all cells express MHC class 1 proteins. NK cells express inhibitory and stimulating receptors. Both positive (stimulating) and negative (inhibiting) signals may be received when an NK cell contacts a target cell. However, inhibitory signals will dominate if the cell the NK cell is interacting with is healthy
NK cell antagonists
These antagonists are decoys that are virally encoded MHC molecules
Dendritic cells
They have similar properties and functions to macrophages. Dendritic cells determine whether and when the innate immune response needs reinforcement with the adaptive immune responses. When adaptive immunity is necessary, dendritic cells in the infected tissue take intact and degraded pathogens to the lymphoid tissues, where they activate T cells in the adaptive immune response. These cells have a star-shaped morphology
How are dendritic cells activated?
By cytokines. The cytokines bind to TLRs on immature dendritic cells to activate the dendritic cells to carry out their functions
Dendritic cell functions (3)
- Process viral proteins and present their peptides on MHC class 2 cell surface receptors
- DCs migrate to draining lymphatics and exchange information between DCs and the naive T cells
- Some viruses infect dendritic cells
DC maturation
DCs take up viral proteins through TLRs present on their surface. They also receive inflammatory cytokines and dead cells, and must take all of these signals into account. After activation by antigens, dendritic cells start to mature. In the endosome, fragments of the antigens are loaded onto MHC class 2 receptors. Activated dendritic cells migrate from the tissue to lymphatic vessels. Dendritic cells are carried in the lymph to the lymph node. T cells then inspect the dendritic cells for the presence of antigen.
Inflammation
An increase in blood flow and capillary permeability, infiltration of phagocytic cells, and tissue damage caused by cytokines and chemokines. Symptoms include redness, heat, pain, and swelling
Chemokines
Recruit immune cells into the tissue. These include IL-8 (CXCL8) and MCP-1
Cytokines
Initially provide local defense, but can enter the circulation when they are produced in large quantities. This causes systemic effects- lethargy, muscle pain, loss of appetite. Includes IL-6, IL-1, and TNF alpha
4 stages of extravasation
- Rolling adhesion
- Tight binding
- Diapedesis
- Migration
Diapedesis
When neutrophils squeeze between the endothelial cells of the blood vessels, guided by a chemokine.
Which interactions allow for strong neutrophil adhesion?
CXCL8 binds to CXCR1 and CXCR2, chemokine receptors on neutrophils. Upon entering the tissue, neutrophil’s gene expression changes, making it more phagocytic
Suppressors of cytokine signaling (Socs)
Act in a negative feedback loop to attenuate signaling, they are not expressed in unstimulated cells. Anti-inflammatory cytokines include TGF-beta and IL-10. There must be a balance between inflammatory and anti-inflammatory cytokines
CD28
A co-stimulatory receptor, which further potentiates the interaction between TCR and MHC class 2 molecules
Exogenous antigen processing by MHC class 2 (6 steps)
- An antigen is taken up into a dendritic cell by endocytosis. As the endosome matures, the pH continues to drop
- At a pH of 5.5 or below, resident proteases cleave the protein into peptides
- Peptides are processed in the Golgi apparatus, and MHC’s invariant chain is degraded
- Vesicles containing the antigen and MHC class 2 molecules fuse. Peptides occupy the groove between 2 MHC class 2 chains
- MHC class 2 molecule is localized to the plasma membrane by endocytosis
- MHC class 2, containing antigen in its groove, presents the antigen to CD4 helper T cells
MHC class 2 structure
It is a heterodimer of the membrane-spanning type I α-chain (34-kDa) and β-chain (29- kDa) glycoproteins. An invariant chain is bound to the dimer. The invariant chain prevents antigen binding to MHC-II by blocking the groove, so it must be degraded by proteases for the antigen to bind
Viral countermeasures against MHC class 2 antigen processing
CMV can downregulate the expression of MHC class 2 molecules
Function of lymph nodes in the immune system
APCs bring antigen to the closest lymph nodes through afferent lymphatic vessels. T and B cells recognize the antigen and undergo a massive amplification. This may cause lymphadenopathy
Gut-associated lymphoid tissue (GALT)
Both M cells and intraepithelial lymphocytes are important in
the transfer of antigen from the intestinal lumen to the
lymphoid tissue in Peyer’s patches, where an immune response can be initiated. M cells are located in the epithelial lining and sample antigens during an infection, then transfer the antigens to the Peyer’s patch so they can be examined by resident T cells and B cells
Cutaneous immune system
The immune system associated with the skin. Components include keratinocytes and Langerhans cells
Keratinocytes
Skin-resident phagocytes, secrete various cytokines, including TNF-α, IL-1, and IL-6; can also synthesize MHC-I and II (Thus, keratinocytes function as APCs)
Langerhans cells
Migratory dendritic cells and are the major antigen-presenting cells in the epidermis. Can migrate to lymph nodes and present antigen
Structure of GALT
The surface of the intestine has epithelial tissue. Beneath that is the basement membrane and submucosal tissue. The submucosal tissue has blood vessels, lymphatic vessels, and Peyer’s patch
Types of effector CD4 T cells (5)
- TH1
- TH2
- TH17
- TFH
- Treg
TH1 cells
Produce immune responses against intracellular pathogens (bacteria, viruses). Differentiation triggered by IL-12
TH2 cells
Produce immune responses against extracellular pathogens (worms, parasites). Differentiation triggered by IL-4
Polarized T cell response
When the cytokines responsible for driving the differentiation of TH1 and TH2 cells are secreted, it results in positive reinforcement- causes the functional effector T cells to drive further differentiation of the same effector T cell type. This can cause rapid expansion of a population of pathogen-specific CD4 T cells, and either TH1 or TH2 cells become dominant. When this occurs, the T-cell response becomes polarized. IL-12 is a cytokine that skews the T cell response toward a TH1 profile.
Treg cell functions (3)
- Regulatory helper cells, development is induced by TGF-β and the absence of IL-6
- Suppress other T cell responses to limit damage and promote healing
- Prevent autoimmunity- cytokine secretion, cell-cell contact, and cytolysis
Differentiation is triggered by IL-6
TH17 transcription factors
RORγT turns on IL-17 gene expression in T cells. IL-17 then goes on to induce epithelial and stromal cells to secrete CXCL8, which is responsible for neutrophil recruitment and activation. Stat3 is also necessary for TH17 differentiation
TH17 functions (3)
- Development induced (by IL-16 and TGF-β) during extracellular bacterial and fungal infections
- Has a key role in maintaining mucosal barriers
- Enhances the neutrophil response
Differentiation triggered by RA
T-bet
A transcription factor that drives naive T cells to become TH1 cells and suppresses TH2 differentiation. When the T cells are exposed to IFN-γ, T-bet is up regulated and GATA3 is down regulated
GATA-3
A transcription factor that drives cells to become TH2 cells and suppresses TH1 differentiation. When T cells are exposed to IL-4, GATA3 is up regulated and T-bet is down regulated
FoxP3
A Treg defining transcription factor, which turns on IL-10 and TGF-β expression in T cells
Where do B and T cells mature?
B cells mature in the bone marrow, T cells mature in the thymus
What happens to B and T cells after they mature?
Once naïve T and B cells have been quality controlled, they move to lymph nodes and the
circulation, awaiting stimulation by a professional antigen-presenting cell
Helper T cell function
The Th cell recognizes antigens bound to MHC class
II molecules and produces cytokines that either- “help” activated B cells to differentiate
into antibody-producing plasma cells (Th2 cytokines). Or- that induce CD8+ cytotoxic T
lymphocytes to kill virus-infected cells (Th1 cytokines)
Neutralizing antibodies
Render a virus particle non-infectious. Not every antibody is neutralizing
Antibody structure
2 heavy chains and 2 light chains, the molecule is Y shaped. Antigens bind to the arms of the Y (Fab region). The hypervariable regions in the Fab section give the specificity to the antibody targeting a specific antigen. The Fc section (stem of the Y) binds to receptors to send signals
Cross-reacting antibodies
Antibodies that can’t neutralize infection
Antibody mechanisms (6)
- Binding to the antigen and tagging it for opsonization by phagocytes- enhances phagocytosis
- Neutralizing the antigen, stopping it from binding to target tissue
- May cause the antigen to agglutinate- enhances phagocytosis and reduces the number of infectious units to deal with
- Activate the classical pathway of complement activation, triggering cell lysis
- Inflammation- disruption of the cell by complement/reactive protein attracts phagocytic and other defensive immune system cells
- Antibody-dependent cell-mediated cytotoxicity- antibodies attached to the target cell cause destruction by non-specific immune system cells
Typical adaptive antibody response
The primary antibody response is modest. The secondary response is rapid and stronger, with many more antibodies being produced. This demonstrates immunological memory. Self limitation- the antibody titer declines with time after each immunization or challenge to the immune system
Serotypes
Some viruses have several serotypes due to differences in their genomes. Every virus serotype generates unique antibodies that can’t cross-react.
Antibody-dependent cell-mediated cytotoxicity (ADCC)
ADCC is a cooperative immune response mediated by innate and adaptive factors. NK cells carry out their innate immune function by recognizing antibodies specific to viral antigens, so antibodies bind to that antigen. NK cells have Fc receptors on their surface which can bind to the Fc region of antibodies, and this is how they are targeted to the infected cell. This is especially effective if the pathogen has subverted the innate immune response or there are no PAMPs are exhibited, as with parasites
Endogenous antigen processing (MHC 1)
MHC class 1 is present on any cells, so the cells can present antigen to CD8 T cells. Inside the cell, some amount of viral proteins will always undergo degradation by proteasomes. Degraded peptides of viral origin can be taken up by channels made by TAP1 and TAP2 proteins, and can be loaded onto MHC class 1 molecules in the ER. The MHC complexes are then trafficked to the Golgi apparatus and then the cell membrane
MHC 1 structure
MHC class 1 is a heterodimer. It has an α chain (43 kDa) and a β2-microglobulin (12 kDa) that
does not span the membrane
Release of the MHC class 1 complex
The MHC class I complex, loaded with peptide, is released from the ER to be transported via the Golgi compartments to the cell surface. There, it is available for interaction with the T-cell receptor of a cytotoxic T cell carrying the CD8 coreceptor
Tap1/Tap2
A heterodimer transporter complex that allows peptides to enter the ER lumen and be loaded onto MHC class 1 molecules
Cross-presentation
Dendritic cells can present antigens to both CD8 and CD4 T cells, which have MHC class 1 and MHC class 2 molecules
Perforin
Secreted by CD8 T cells, form pores in the plasma membrane
Affects of perforin (2)
- Release of cytoplasmic content through pores, causing cell death
- Injection of Granzymes that eventually activate Caspase mediated apoptosis
Attributes of the host response (4)
- Speed- presence of lymph nodes located near sites of infection
- Diversity and specificity of T and B cells- due to TCRs, there are more than 20 million distinct T cell specificities. Receptor genes also undergo random somatic rearrangement after recognition, and then are selected for high affinity
- Immunological memory after the infection is cleared
- Self control
Steps involved in inflammation (5)
- At the viral entry site, localized inflammation is triggered
- Chemokines are secreted attract immune cells
- Endothelial adhesion molecules bind immune cells
- Adhesion and entry of immune cells into the infected area
- Cytokine release activate immune cells and cause inflammation
Determinants of the nature and extent of inflammation
Tissue site and the virus (cytopathic or not). Inflammation can be more damaging in some tissues than others, like inflammation in the brain can be very damaging
