T-Cells: Development and Activation Flashcards
Danger Theory: The immune system protects the body from what three types of danger? (danger signals)
- Pathogens (Bacteria, viruses, fungi, parasites)
- Unusual tissue growth
- Damaged cells and tissues (housekeeping ability)
Danger signals can be given out by distressed cells and bacteria
Ex. Heat Shock Proteins
Ex. Uric acid is produced by damaged cells; signals immune system
Three functions of T lymphocytes
- Production of cytokines
- Cytotoxicity (kill other cells)
- Control of other immune cells
Major role of B lymphocytes
Production of antibodies by plasma cells
Plasma cells are a stage of B lymphocytes that are able to produce antibodies
Primary and Secondary Immune Responses (and tissue grafts)
If you stimulate with A a second time, the response will be much greater
If you give tissue graft to a patient and it rejects it the first time, the rejection to the same type of tissue graft will be even stronger the second time
Two major subgroups of T cells
CD4+ (TH):
Helper cells, get immune system going and direct it
CD8+ (Tc):
Cytotoxic (killing) ability
Th1-cell mediated immunity (CMI)
[CD4+, TH]
Produce IFNg and TNFa (Type IV Hypersensitivity)
Respond to intracellular pathogens
Steer the immune system; important in response to intracellular pathogens and viruses (listeria or TB)
Th2-Humoral Immunity
[CD4+, TH]
Produce IL-4, IL-5, IL-13 (Type I Hypersensitivity)
Controls antibody production
Helminths (parasitic worms), allergic reactions, extracellular pathogens
Th17
[CD4+, TH]
Produce IL-17 cytokine
Acts upon a number of cell types
Important in defense against extracellular bacteria and fungi
(Candida albicans)
Also play a role in defense against TB, but much less critical/well-defined
TReg
[CD4+, TH]
Can suppress (inhibit) the effector functions of CD4+ and CD8+ T cells.
AKA downregulate the immune response
TReg cells account for 5-10% of the CD4+ cells and express:
CD25 (part of cytokine receptor)
FOXP3 (surface molecule you can detect upon TReg)
Cross-regulation of Th1/Th2
Th1 produces IFNa, IFNg IFNa, IFNg inhibit Th2 IFNa, IFNg lead to macrophage activation IFNa, IFNg induce more Th1 Activated macrophages release IL-12 IL-12 induce more Th1
Th2 produce IL-3, IL-4, IL-5
IL-3 promote Mast Cell growth (induce allergic responses)
IL-4, IL-5 induce B cell activation, which produce antibodies
IL-3, IL-4, IL-5 induce more Th2
IL-3, IL-4, IL-5 inhibit Th1
In certain responses, either Th1 or Th2 is usually dominant
Tc (Activation, 2 pathways)
Tc is activated by Th1 cytokines
Killing requires direct contact and conjugate formation
Pathway 1: Cytoplasmic granules = perforin + granzymes»_space; apoptosis (via granzymes)
Pathway 2: Fas-Fas ligand interactions»_space; apoptosis
Similar cytotoxicity mechanisms to NK and NKT cells
Antigen Presenting Cells (APC)
Types:
B cells, macrophages, dendritic cells
Can enzymatically process antigen
Present digested fragments to Th cells (that then stimulate Th cells)
Do this via MHCII molecules
B and T cells with antigen presentation
B cells can interact with antigens in isolation
T cells must have antigens presented to them (via APC)
Epitope
The part of the antigen (small part) that is recognized by the lymphocyte receptor
Antigenic determinant
T and B cells recognize different types of epitopes (usually)
For any antigen that contain many epitopes, some will be more presented more than others (immunodominant)
MHC I
Found on all nucleated cells
Present antigen to CD8+ (Tc)
Saying “kill me”
HLA-A, HLA-B, HLA-C
MHC II
Found only on APC
Presents antigen to CD4+ (Th) cells
Stimulating an immune response
HLA-DP, HLA-DQ, HLA-DR
Chains of MHCI and type of antigen it presents
Consists of:
- Polymorphic heavy (a chain): highly variable among individuals
- Non-polymorphic (constant) light chain (B-2 microglobulin): Essential for expression of MHCI, but not attached to MHCI heavy chain or the cell surface; not encoded within the MHC
Presents:
Endogenous antigen (formed inside the host cell)
Viruses, tumors
(Viral: takes over cell’s ability to produce proteins; viral antigens produced as if they are the cells own proteins)
Presents to CD8+ Tc cells
Can be increased by: IFNa,b,g
Chains of MHCII and type of antigen it presents
Consists of:
Polymorphic a and B chains (both encoded within MHC)
Found on specialized APCs (dendritic, macrophage, B cells)
Presents: Exogenous antigen (originate outside of APC; ex. fragments of bacteria, viruses caught between cells, vaccines)
Presents only to CD4+ Th cells
Can be increased by: IFNg, a
Clonal selection (Process and Cell types)
All T and B cells have receptors for antigens
Genes are randomly changed around to get unique receptors that recognize antigens (somatic recombination)
Transposons “jumping genes”; gene segments detach, move up chromosome and reattach later on
T cells develop and produce millions of antigen receptors
The one that fits the antigen will undergo a change, receive a stimulus that activates it
The ones that don’t recognize antigens will fade away and die
The cell that by chance is specific for that antigen, you now get thousands of cells specific for that antigen (why your response is much greater the second time)
Cell types:
mostly Effector cells: T cells and plasma cells for B cells
Memory cells: Stay in lymph nodes; could be re-stimulated at later date
Via mitosis: identical parent and daughter cells
If this is not regulated, eventually you will end up with a tumor
Primary, Secondary, and Tertiary Lymphoid Tissue
1: Thymus (T) and Bone marrow (B)
2: Lymph nodes and tissues
3: Remaining areas where lymphoid cells are found
Which MHC molecules are found on macrophages?
Both
MHC1: Macrophage is a nucleated cell
MHC2: Macrophage is an APC
Thymus (what do T cells come in contact with? what develops on T cells? DN, DP, SP)
Bilobed organ lying over the heart (Sail shaped)
Contains many T lymphocytes at various stages of development
Committed T cells pass through the thymus where they undergo a selection process
Also contains thymic epithelial cells which express MHC molecules
These MHC molecules contain our own antigen; we do not want T cells to respond to this
In thymus:
- TCR develops
- Surface molecules change
- And CD3, CD4, CD8 (associated with TCR)
DN: CD3+ but DN for CD4+ and CD8+
DP: CD3+ and DP for CD4+ and CD8+
SP: CD3+ and either CD4+ or CD8+ (SP ratio ~2:1)
Once either 4 or 8, it’ll interact with MHCI or II and then develop
CBC w/ diff would be essential to elucidate the total lymphocyte count
Bone Marrow
Site of lymphocyte origin
T and B cells being existence here
T cells leave underdeveloped for the thymus
B cells mature and undergo type of selection to remove potential autoreactive cells
Movement through the lymphoid system
- Lymph moved along the vessels by contraction of the body’s muscles in a ONE-WAY system
> Lack of effective muscle contraction can cause this movement to cease
» Causes edema in the tissues (elephantiasis) - Foreign antigens which enter the connective tissue are carried by the lymphatics to the nearest lymph node (draining lymph node)
> You can get an enlarged lymph node from an infection (draining LN); it’s not carrying out all the activity required to get rid of that antigen
Chronic Wuchereria Bancrofti Infection
After many years of infection
Microfilaria block lymphatic vessels, resulting in edema in legs, scrotum, and breasts
Lymph Node (APCs, 3 parts, blood supply)
Direct entity with own blood supply and own lymphatic vessels going out
Where antigen presentation takes place
Cortex: B cells in germinal centers (follicles- collection of cells)
Paracortex: Mainly Th cells
Medulla: Plasma cells
Macrophages and dendritic cells found in cortex and paracortex (outer regions)
Lymph, fluid that drains through these tissues, holds APCs that sample microbes circulating
Dendritic cells pick up the microbes and transfer them to lymph nodes concentrating them there for immune activation
B cells > Plasma cells
When B cells form plasma cells, they go to the bone marrow and medulla in lymph node and start secreting the antibody
They don’t need to be at the site of infection because antibodies can move around through the blood stream
Spleen
Largest of the lymphoid organs, but not connected to the rest of the lymphoid system
Hilum where the splenic artery and vein leave
No lymphatic vessels supplying the organ
Significant role in blood-borne diseases (malaria, capsulated bacteria)
Also site of removal of damaged RBCs and platelets
Filters blood capturing microbial antigens that have been concentrated by dendritic and macrophages
Abundant phagocytes (destroy blood microbes)
B cells located in follicles and white pulp of the spleen
Other lymphoid tissues
(Spleen, Thymus)
Appendix
Tonsils
Adenoids
Peyer’s patches
GALT
Gut associated lymphoid tissue
Peyer’s patches
Appendix
GALT+BALT = MALT
Mucosal-associated lymphoid tissue
BALT
Bronchial associated lymphoid tissue
Respiratory tract lymphoid tissue
GALT+BALT = MALT
Mucosal-associated lymphoid tissue
How are antigens transported from mucosal surfaces to the lymphoid system?
M cells:
Microfold
Membranous cells
Lymphocyte Recirculation
- Lymphocytes leave the blood circulation and enter the lymphatic system at lymph nodes
- They leave the venous system through specialized epithelial cells
HEV: High endothelial venules
By diapedesis or extravasation - Re-enter venous circulation via thoracic duct
Which enters the left subclavian vein
Langerhans cells
Type of dendritic cell of cutaneous surface (skin)
Capture antigen which penetrates the skin and carry to draining lymph node where they process and present the antigens to T cells in the paracortex
TCRgd cells
Intraepidermal lymphocytes that are thought to be a first response to infection
Definition of Antigen
Used to be: molecules that induced antibody responses
Now: any molecule that is recognized by BCR or TCR
Can be large and the portion of the antigen bound by receptor is called the epitope
Haptens
NOT antigens
Small molecules that by themselves cannot induce an immune response
They are antigens but are not immunogenic
They induce an immune response when attached to a larger protein (often host’s own protein)
Ex. nickel, penicillin, urushiol (poison ivy)
Adjuvant
Most isolated antigens require this to induce an immune response
Third party compounds or substances which stimulate the immune system
There are several in common use and their mode of action varies from type to type
- Non-specifically stimulate lymphocytes
- Prolong antigen persistence
- Induce receptors on accessory cells
T Cell Epitopes
- Much better defined than B cell epitopes
- Usually between 8-11 AA for presentation by MHC I
- Somewhere between 13-17 AA for MHC II
* We don’t have as many MHC types as we do T cell receptors*
Must interact with MHC and T cell receptor at the same time
AA comprising the epitope must be sequential
T cell receptor is precise, MHC is broad
CD40L (ligand)
T cell surface molecule
Interacts with CD40 on APC
Important for antibody class switching Lack leads to Hyper IgM syndrome (these patients lack CD40 and can't switch antibodies)
CD28
T cell surface molecule
Interacts with B7.1 (CD80) and B7.2 (CD86) on APC
Important in providing second signal to activate naiive T cells
Lack of interaction can lead to anergy
Counterpart to CTLA-4
CTLA-4
T cell surface molecule
Constitutively expressed on TRegs and induced on activated T cells
Also interacts with B7.1 and B7.2
Acts to switch OFF T cell function (downregulates)
TCR
Heterodimer consisting of a or B chain
Both chains anchored in cell membrane
Like Ig, T cell receptor consists of variable and constant region
Constant: AA that are the same across lots of different receptor types
Variable: variability that can interact with antigen
TCR genes do not undergo somatic hypermuation
T cell does not develop further after it leaves thymus
TCR requires CD3 function to function
Somatic Hypermutation
In B cells
Additional nucleotide substitutions take place during activation and division of the cells
Some of these substitutions result in better binding between Ig and antigen
These B cells are then clonally expanded
(Further rearrangement after B cells leave the bone marrow to get extra variability)
T cells do NOT do this
Cellular Interactions between B and T cells
Neither usually act in isolation
B cells require T cells to function
T cells require APC to present antigen to them
BCL-2
Gene that encodes for BCL-2 protein
Expression of BCL-2 inhibits apoptosis and is found in certain lymphomas; overexpression could lead to malignancy
Particularly B cell follicular lymphoma
Regulation of Hematopoiesis
Aka production of cells out of bone marrow
FAS
Encodes for FAS protein
When Fas interacts with its ligand, FasL, apoptosis of the cell occurs
Regulation of Hematopoiesis
Aka production of cells out of bone marrow
Early development in Hematopoiesis (three precursors & life span)
Blood cells arise from a common pluripotent stem cell
Three types of precursors
- Erythroid progenitors (RBCs, platelets) [life span 120 days]
- Myeloid committed precursor cells (neutrophils, eosinophils) [life span days or weeks]
- Lymphoid committed precursor cells [can live for years]
Leukocytes
WBCs
Adaptive and innate responses
Originate in bone marrow
Ability to recognize foreign invaders and destroy them
Three main groups of lymphocytes (and type of receptors)
B cells and T cells
Both possess antigen receptors
NK cells
Don’t have specific antigen receptors, making them a part of innate immune system. But they use ADCC (antibody-dependent cellular cytotoxicity aka utilizing antibodies to recognize specific antigens)
EBV
Affects B cells and causes them to divide
Would grow exponentially unless they are regulated
T cells normally regulate, can recognize that they’re infected with a virus and kill them.
When a T cell kills a B cell, you feel awful.
AKA Mononucleosis
Need this process thought because if the T cells didn’t kill the B cells, you’d die
Co-dominant
MHC antigens are co-dominant
You express what you get from your mom and dad
Allelic exclusion
TCR and BCR
Only get one T or B cell receptor expressed
If one is expressed, the other stops working
True allelic exclusion is relatively rare
Haplotype
Combination of alleles at linked loci found on one chromosome
Often used with reference to MHC
Polymorphism (and of MHCI and MHCII, genetics)
Existence of multiple alleles at a particular gene locus
MHCI: only have 6 MHCI molecules; only the a/heavy chain has polymorphism
MHCII: a & B chains are polymorphic; and a & B chains can make different combos too; a lot greater diversity; for some people up to ~21 different MHCII molecules on a given APC
Each individual inherits one allele from each parent BUT
Not necessarily the same as your parents because you could have an a pair with different B that’s different
Specificity of (broad and precise) Antigen with MHC and TCR / vaccines
Antigen binds to MHC with broad specificity
Antigen binds to TCR with precise specificity
Because we only have a limited number of MHC molecules, there could be an antigen that we can’t present.
As vaccines become more precise, we could possibly have someone that can’t present antigen to T cells
Ex. HepB vaccine can’t be presented by certain individuals; it can’t sit in the MHC cleft
Even a good vaccine will only work on about 90% of population
CD34+
Stem cells in the bone marrow
Precursors ot thymocytes
Crucial because indicator of a stem cell
The molecule they use to pull the stem cell out in transfusions
Positive Selection
Functioning T cells must be able to bind to MHC complex
If DP cells bind to MHCI, they become CD8+ SP cells
If DP cells bind to MHCII, they become CD4+ SP cells
Cells that cannot bind undergo apoptosis
Negative Selection (and goldilocks idea)
For potential disease causing cells
That could respond to self antigen presented by MHC
Goldilocks idea:
Thymocytes that do not bind to MHC do not survive
Thymocytes that bind to self MHC and self antigen are also destroyed
Those with intermediate affinity survive
Central Tolerance
Occurs in thymus
Cells that respond strongly to self MHC and self antigen are destroyed
Peripheral Tolerance
When self reacting T and B cells are in an unreactive state to self antigens
When cells leave the Thymus, they need to learn not to respond to our own antigens (like food or microbial antigens)
Mechanisms of Peripheral Tolerance
- Ignorance: Autoreactive T cells never encounter their cognate Ag except by accident
Ex. Orchitis: Patient with mumps; inflammation of vesicles in testes which allows lymphocytes to go through there; they can become sterile because lymphocytes encounter sperm for the first time and mount an immune response to them - Deletion: Self-specific peripheral T cells are destroyed after TCR engagement; Negative selection is leaky though
- Anergy: State of unresponsiveness induced upon self-Ag recognition
- Foxp3+ Treg cell-mediated suppression of dangerous T cell responses against self-Ag
Prevent autoimmune responses
Treg
Possess high levels of FoxP3 and CD25 (part of IL-2 receptor)
Produced by stimulating CD4+ T cells with TGFB (transforming growth factor beta)
Can inhibit T cells via cytokines
>IL-10 and TGFB (can switch off other T cells)
Why might live viral vaccines have complications causing disease in patients with T cell defects?
There would be no immediate response to vaccination.
Defects in antibody production from B cells may hinder long term protection from the vaccine but would not lead to acute infection from vaccination
Surface makers on NK cells
CD16/56
