Cell Mediated Immunity Flashcards
Cell Mediated Immunity
The adaptive immune system that functions to combat intracellular pathogens
T-cell interactions during cell-mediated immunity
Interactions with:
- Phagocytes
- Infected host cells
- B lymphocytes
Epitope
That part of an antigen that is recognized by lymphocyte antigen receptors (also known as antigenic determinant)
C-region:
V-region:
Constant region: Genetically conserved receptor domain
Variable region: genetically diverse antigen recognition domain
Affinity for antigen (B-cells and T-cells)
BCR has higher initial affinity which increases during response
TCR affinity is fixed
T-cells are ________ restricted
MHC
What provides the mitogenic signal for developing lymphocytes to proliferate and where is it produced
IL7 produced by bone marrow stromal cells
Failures at each checkpoint (1 - 3)
1) Failure to express pre-antigen receptor (β chain)
2) Failure to express antigen receptor (α chain)
3) Negative selection (strong antigen recognition)
TCR (T-cell receptor) structure
αβ T-cells - Most abundant - MHC restricted γδ T-cells - Common in gut mucosa (recognize lipids) - Not MHC-restricted
The variable region of the TCRβ chain is composed of three gene segments
V - Variable
D - Diversity
J - Joining
Recombination events making up first checkpoint
- First recombination event is the heavy chain D and J exons
- Second recombination of V with DJ
- VDJ recombination with TCRβ constant region
- The heavy chain transcript (VDJ-C) is processed and expressed within the cell and then at the cell surface with a surrogate light chain
Formation of the intact TCRαβ protein (Second checkpoint)
TCRα chain V and J recombine and VJ recombine with a C segment (VJ-C) to form α chain for TCR - combines with β chain to form the intact TCRαβ protein
What are the 3 regions of hypervariability in the variable region of the TCRα and TCRβ chains
CDR1
CDR2
CDR3
What is the purpose of CDRs?
Encode specific amino acid residues in the TCR protein that contact the antigen
2 mechanisms of antigenic diversity
Combinatorial - variation amongst possible VDJ or VJ combinations
Junctional: Removal of nucleotides AND addition of nucleotides by TdT enzyme; strand repair during recombination process
Total number of possible epitopes with combinatorial and junctional diversity
TCR: 10^16
Immunoglobin: 10^11
Location of induction and effector phases of cell mediated immunity
Induction phase: lymphatic tissues; spleen
Effector phase: Peripheral tissues (site of infection)
General activation of T cells
- Microbial antigens traffic to peripheral lymphoid tissue inside activated phagocytic antigen-presenting cells (APC)
- In combination with antigen-presentation these T cells receive signals from the microbe or from the innate immune system (cytokines or pattern recognition receptors) which enhance their activation (co-stimulatory second signal)
- T cells only recognize and respond to those antigenic peptides displayed by MHC
Steps in T Cell gaining Effector functions
1) Antigen recognition
2) Activation
3) Clonal Expansion
4) Differentiation
5) Effector functions
Recognition of antigen by T cell increases _______ (integrin) affinity
LFA1 (anchor naive T cells to APC during antigen presentation)
First Signal
T cell receptor and the CD4 or CD8 co-receptor together recognize MHC: antigen peptide complexes on the APC cell surface
\_\_\_\_\_\_ recognize antigen presented by MHC class II \_\_\_\_\_\_ recognize antigen presented by MHC class I
TCR-CD4; TCR-CD8
How many TCR-co-receptors need to be engaged simultaneously to activate naive T-cells?
two or more
CD4+ T cells become:
CD8+ T cells become:
Cytokine-producing helper cells
Cytolytic T-lymphocytes (CTLs)
Second Signal
T-Cell CD28 interaction with co-stimulatory molecule on APC cell surface
Co-stimulatory molecule on APC
B7
CD3
Signaling receptor expressed on all T-cells
Marker used to find T-Cells in the body
CD28
Co-stimulator receptor activated by ITAM
Early in response
CTLA4
Co-stimulator receptor inhibited by ITIM (off signal)
Late in response
ICAM1
Adhesion molecule on APC
ITAM
Immunoreceptor activation motif - ACTIVATING SIGNAL
found on CD3 and CD28
Professional APCs
Dendritic Cell
Activated macrophage
B-Cell
Upon ingestion of antigen, the macrophage will:
- Upregulate costimulatory molecules (B7)
- Increase levels of MHC
- Secrete cytokines (IL-12)
B-cell Function
B cell APC bind specific antigen via their surface immunoglobulin. These antigens are processed and presented by MHC class II with co-stimulatory molecules and efficiently present antigen and activate T-cells
IL-2
T-Cell Proliferation Cytokine
- Produced by an activated T-cell
- T-cell proliferation begins 1-2 days after activation
- Switch in IL-2 receptor affinity during proliferation
T-cell Clones
Daughter T cells of proliferating cells that express identical TCR and co-receptor (CD4 or CD8) and recognize the same antigen to which the naive T cell recognized
CBC w/ differential (CD4 and CD8 amounts after clone production)
CD4+: may expand 100-1000 fold during infection
CD8+: can expand 10,000 fold and may comprise 10-20% of all serum lymphocytes during peak of viral infection
Step 2: Clonal Expansion
- T cell activation by antigen + co-stimulator
- Secretion of IL-2
- Expression of IL2Rα chain; formation of high affinity IL-2Rαβγ complex
- IL-2 induced T-cell proliferation
Step 3: Differentiation
Effector and Memory cells
- Differentiation occurs simultaneously with clonal expansion
- Effector cells appear 3-4 days after initial infection
- Migrate out of the peripheral lymphoid tissues and migrate to the site of infection
CD4+ helper T cell cytokines
CD40L: binds to CD40 (APC) providing an amplification signal to maintain the immune response inside the APC
CD4+ T cells - Effector cell subsets
IFNγ, IL12: differentiate to Th1 cells
IL4: differentiate to Th2 cells
TGFβ, IL6, IL23: differentiate into Th17 cells
Memory T-Cells
Survive after the infection has been successfully eradicated and the innate immune response has resolved
There are more CD8+ memory T cells than CD4+ memory T cells
Effector T cells don’t require ______ to function
Costimulaiton
CD4+ T cells - Effector subsets and Actions
Th1: Activate macrophage → Kill intracellular bacteria
Th2: Activate B cells → Secrete antibodies to parasites/allergens
Th17: Activate PMNs → kill bacteria and fungi, involved in autoimmune responses
CD8+ T cells activated by:
1) Direct = antigen + presenting cell
2) Indirect = antigen + Th1 help
Lymphocyte recirculation: Naive T lymphocytes
Recirculate from blood to peripheral immune tissues until an antigen is recognized
Lymphocyte recirculation: Effector lymphocytes
Leave the peripheral immune tissues through the efferent lymphatic vessels. Recruitment to sites of antigen entry is specific
Effector T Cells at site of infection
TNF and IL-1 activation of endothelial cells and elevated production of chemokines occurs as a function of innate immunity
Chemokines
Bind and accumulate on endotehlial surface → Establish high concentration at site
In the periphery, Effector T Cells lose expression of _______ which inhibits trafficking back to lymphoid tissue
They express ____________
L-Selectin
E&P selectin
Higher affinity forms of what integrins enhance tighter adhesion to endothelium at site of infection?
LFA-1
VLA-4
Inflammation
Complex reaction of multiple components of the innate immune system in vascularized tissues
Steps of inflammation
1) Bacteria trigger macrophages to release cytokines and chemokines
2) Vasodilation and increased vascular permeability cause redness, heat, and swelling
3) Inflammatory cells migrate into tissue, releasing inflammatory mediators that cause pain
Relationship of T cell homing and antigen recognition
T cell homing is INDEPENDENT of antigen recognition (non selective migration)
Effector T Cell tracking to lymphatic tissues
CCR7: chemokine receptor
L-Selectin
Effector T Cell tracking to peripheral/regional tissues
CXCR10
E or P selectin
Th1 Immune reaction
Macrophage activation; IgG production, releases CD40
Th2 immune reaction
Mast cell, eosinophil activation; IgE production; alternative macrophage activaton
Th17 Immune reaction
Neutrophilic, monocytic inflammation
Th1 cells induce _______ ________ in B cells so that those cells produce complement binding and ________ antibodies
Isotope switching; opsonizing
______ from the Effector T Cell and ________ from the macrophage create a positive feedback loop to amplify and maintain the cell mediated immune response
IFNγ ; IL-12
Aside from IL-4, what other cytokines are important for Th2 cells and what are their functions?
IL-13: Intestinal mucous secretion and peristalsis; alternative macrophage activation (tissue repair)
IL-5: Eosinophil activation
IL-4 alone: isotope switching in B cells
Th17 cells produce_______and ______ and have several functions:
IL-17;IL-22
1) Increase recruitment of PMNs, monocytes to site of infection
2) Maintain epithelial barrier integrity
3) Implicated in host defense against extracellular bacteria and fungi
CD8+ T cells (CTLs) mechanism of killing
Secrete proteins which create pores in the infected cell membrane (apoptosis)
1) Perforins: polymerizes to form a pore in target cell membrane
2) Granzymes: Serine proteases which activate apoptosis once in the infected cell cytoplasm
3) Express Fas Ligand which can induce apoptosis by finding Fas Receptor on target cells
CD4+ and CD8+ cooperation
T Cell activation: Naive CD8+ cells recognize antigen displayed by MHC class I but the APC co-stimulatory signal is weak Activated CD4+ release cytokines (IFNγ) further activate the APC upregulating additional costimulatory molecules
Super Antigen
Toxin outside the MHC binding cleft - causes non-clonal expansion
What is the function of IFNγ?
increase animicrobial killing in macrophages
What is the function of IL-12?
differentate CD4+ T cells into Th1 Effector T cells
