Adaptive Immunity: Specific Defenses of the Host |
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Components: Cells (T-Lymphocytes, Antigen Presenting Cells, Natural Killer Cells) and Chemicals
T-cells are produced by stem cells in the bone marrow (like B-cells) and migrate to the thymus to mature.
Most immature T-cells are eliminated in the thymus in a process similar to the clonal deletion B-cells undergo.
After maturation, T-cells leave the thymus and move to lymphoid tissues, where they are most likely to encounter pathogens that are more susceptible to the cellular immune system.
In the intestinal tract most pathogens can only gain access to the body by passing through M cells (microfold cells), which are strategically positioned over lymphoid tissues like Peyer's patches. There the pathogens find antigen presenting cells and T-cells waiting.
T-cells are classified by function and cell surface antigens (cluster differentiation antigens, or CDs, which also facilitate T-cell receptor binding to antigen) into two major classes:
T-cells bind and recognize their specific antigen through an antigen receptor, which is known as the T-cell receptor (TCR).
The TCR will bind to the antigen it is specific for only when the antigen is bound to a Human Leukocyte Antigen (HLA molecule, although you may be more familiar with the term MHC) on the surface of some other cell.
Human Leukocyte Antigens, or tissue antigens, are glycoproteins that are present on almost every cell in the body. HLA molecules have a groove along the top of the molecule (the peptide binding site) that binds a small piece (peptide) of a larger protein that has been digested.
A peptide is inserted in the peptide binding site of an HLA molecule inside the cell and the HLA-peptide complex is translocated to the cell surface.
Making the antigen available to T-cell receptors in this way is known as antigen presentation.
There are two classes of HLA molecules, Class I and Class II.
Class I HLAs are coded for by three different genes, Class I A, Class I B, and Class I C. Class I molecules are present on all nucleated cells in the body and are recognized by CD8+ T-cells.
Class I HLAs present "internal foreign antigens" like viral antigens and tumor antigens (which look foreign because they are mutant normal peptides).
Class II HLAs are coded for by three different genes as well, the DR, DP, and DQ genes. Class II molecules are present on antigen presenting cells (APCs), which include macrophages, dendritic cells, and B-cells.
Class II HLAs are recognized by CD4+ T-cells.
Class II HLAs present "exogenous foreign antigens", things that have been phagocytized and broken down within APCs.
Normally, HLA molecules have a small piece of endogenous self-peptide, a piece of some normal self protein that has "worn out" and been recycled, bound to their antigen binding site.
T-cells "dock" with the HLA-peptide complex, recognize it as "self", and go on about their business. This is called immune survellience.
That's great, but the purpose of HLA molecules is to present foreign antigens to T-cells, ramp up an immune response, and eliminate the threat.
So how does this work?
If a foreign peptide is bound to the antigen binding site of the HLA molecule the T-cell will recognize the complex as "foreign" and respond appropriately.
But - In order to respond to an antigen, the T-cell has to be activated first.
The first step in T-cell activation is binding of the T-cell to HLA-antigen complex it is specific for on the surface of an APC (thats why they're called antigen presenting cells).
The second step is the requirement for the T-cell to recieve a co-stimulatory signal. Co-stimulation may be the result of interaction of the CD28 protein on the surface of T-cells and B-7 proteins on the surface of APCs or stimulation of the T-cells by cytokines, in particular IL-2, or a number of other interactions (this is somewhat simplified, but go with it).
Without co-stimulation the T-cell won't respond to its antigen - it becomes anergized or tolerized.
Since non-antigen presenting cells don't have co-stimulatory molecules, like B-7, on their surface they can't activate T-cells.
The bottom line here is this: In order to become activated, naive T-cells must recognize their specific antigen by binding between their T-cell receptor and the appropriate HLA-antigen complex on the surface of an APC and recieve a co-stimulatory signal.
When activated, a T-cell will clonally proliferate and produce two genetically identical but functionally different populations.
Effector T-cells (cytotoxic T-cells or helper T-cells) deal with the antigen immediately.
Memory T-cells have the same antigen specificity and respond much more quickly and strongly to that antigen if it is encountered again.
Helper T-cells (CD4+)
Th1 secrete IL-2, gamma-IFN, TNF-ß
Drives cell-mediated responses (stimulates CD8+ T-cells and high levels of gamma-IFN will stimulate phagocytes to kill internal pathogens)
Th2 secrete IL-4, IL-5, IL-6, IL-10
Drives humoral responses (stimulates B-cells)
Antigen presenting cells phagocytize external antigens, break them down in phagolysomes, and put peptide fragments in the peptide binding site of Class II HLAs.
The Class II HLA-peptide complex is then moved to the surface of the APC where it can be recognized by an appropriate CD4+ T-cell.
The act of phagocytosis will stimulate macrophages to secrete IL-1, which will co-stimulate CD4+ T-cells when they bind to the HLA-peptide complex.
When CD4+ T-cells are activated in this way they secrete IL-2, which stimulates macrophages, stimulates CD8+ T-cells, stimulates B-cells, and self stimulates the activated CD4+ T-cells. IL-2 works like a growth factor.
Other CD4+ T-cells
Tfh-cells
When activated by antigen presentation by dendritic cells and IL-21 + IL-6 they differentiate from Th1 and Th2 cells and collect in B-cell follicles in lymph nodes.
Stimulate B-cells to undergo class switching (except IgE), induce affinity maturation, and stimulate formation of memory B-cells
Th17 cells
Another subset of CD4+ T-cells, activated by antigen presentation and exposure to TGF-B and IL-21.
Upregulate receptors for IL-23, which stimulates rapid proliferation.
Situated in the skin and the lining of the GI tract, Th17 cells are positioned to attack bacteria on those surfaces. They do this by secreting defensins and recruiting scavenging cells, especially neutrophils, to the site (by secreting IL-17, the cytokine they are named for). The result: clearing away of the invaders with accompanying inflammation.)
Cytotoxic T-cells (CD8+)
What about antigen presentation and activation of CD8+ T-cells?
Same deal, except the antigen is presented bound to a Class I HLA molecule. APCs can take up viral particles by phagocytizing virally-infected host cells or through gap junctions between the APC and virally-infected cell.
B7 proteins on APCs bind CD28 on the T-cells and co-stimulate them to become activated.
CD8+ T-cells kill virally infected cells and tumor cells when activated by secreting perforin, granzymes, and expressing a protein called FAS-ligand on their cell surface.
- Perforin creates channels in the target cell membrane.
- Granzymes enter the target cell through the channels and turn on enzymes that induce apoptosis in the target cell.
- FAS-ligand binds to a receptor protein on the target cell called FAS. This interaction also stimulates the tartet cell to undergo apoptosis.
Delayed hypersensitivity T-cells
Mostly Th1 cells, some CD8+
Secrete IL-2, activate macrophages
Tuberculosis, allergic reactions to poison ivy, transplant rejection
Regulatory T-cells
Probably a subset of CD4+ T-cells, stimulated by IL-2 and TGF-B minus IL-6.
Suppress immune responses (wind things down).
Secrete IL-10 and inhibit Th1, Th2 and Th17 cells. May also bind to B7 proteins and inhibit co-stimulation of other T-cells.
There may also be some participation by CD8+ T-cells.
Macrophages, dendritic cells, Langerhans cells, and B-cells are all capable of antigen presentation. Dendritic cells need to be fully activated to present antign and activate lymphocytes - need danger signals (which aren't provided by tumor cells/fragments).
The most efficient means of stimulating dendritic cell maturation is binding of TLRs on dendritic cells to PAMPs, which activates cytokine genes and activates the dendritic cells. Cytokines secreted include:
interleukin 12 (IL-12) which stimulates the production of Th1 cells
interleukin 23 (IL-23) which further stimulates the rapid proliferation of Th17 cells
interleukin 6 (IL-6), which interferes with the ability of regulatory T cells to suppress the responses of effector T cells to antigen.(Situated in the skin and the lining of the GI tract, Th17 cells are positioned to attack bacteria on those surfaces. They do this by secreting defensins and recruiting scavenging cells, especially neutrophils, to the site (by secreting IL-17, the cytokine they are named for). The result: clearing away of the invaders with accompanying inflammation.)
Tumor cells can be more vulnerable to heat (fever) than normal cells. Fever produces more tumor cell debris and the higher antigen load is more likely to activate the immune system.
Many vaccines must contain not only the antigen but also adjuvants to be effective. Several adjuvants contain PAMPs, and their stimulus to the innate immune system (APCs) enhances the response of the adaptive immune system to the antigen in the vaccine. Just like attenuated or killed vaccines elicit greater response compared to single antigens exposure to multiple PAMPs stimulates a greater immune response.
Dendritic Cell
Activated macrophages
Natural killer cells
Uncertain lineage, no CD4 or CD8 antigens
Not HLA restricted but seem to be Class I “mediated” - have two receptors, an activating receptor that binds to ubiquitin on cell surfaces and an inhibiting receptor that binds to HLA Class I molecules.
If the HLA molecule is disrupted (may be an alteration inside the plasma membrane of the target cell rather than complete loss of the HLA molecule) the NK cell is uninhibited and kills.
Antibodies attached to target cells cause destruction by non-specific immune system cells (NK cells, macrophages, eosinophils).
Interleukins – something like 41 identified, known, communicate between leukocytes.
Interferons - protect cells against viruses, stimulate macrophages and neutrophils to phagocytize bacteria, stimulate macrophages and NK cells to attack tumor cells, and stimulate TH1 cells, which drive cell-mediated reactions.
Very high levels of gamma-IFN stimulates cytotoxic T-cells.
Chemokines - chemotactic for leukocytes.
For a little more cytokine information click here.
