T-Cells Part I and II Flashcards
T Helper Cells
How many kinds are there?
What surface marker do they ALL express?
There are 5 main kinds of helper T cells, and one killer T cell. Let’s start with the hel pers (so called because they ‘help’ other cells do things).
► They also all express the surface marker CD4
Where are precursor T helper cells usually located?
What celly types brings them the antigen for presentation?
What determines what type of cell they become?
Most T helper cells begin as an undecided precursor: we’ll call it Th0 (zero).
These cells are found in the paracortex of lymph nodes, and corresponding positions in other secondary lymphoid tissues.
When their correct antigen is brought to them by dendritic cells (DC), they begin to divide and differentiate, becoming either Th1, Th17, Th2, Tfh, or Treg cells.
► The previous experience of the DC — the conditions in the periphery when it was stimulated, what TLR were engaged, what cytokines and chemokines predominated — is the main determinant of the Th0’s ultimate progeny.
Th1 Cells
How were they originally called?
What is the most important lymphokine secreted by Th1 cells?
Interferon gamma is a chemoattractant for what other immune cells?
Other than an antigen, what lymphokine activates Th1 cells?
What cytokines are released by macrophages to increase inflammation response?
What other citokine is secreted by Th1, which helps activate CTL cells once they recgonize an antigen?
They were originally called ‘delayed hypersensitivity T cells’.
-> After activation and proliferation in the lymph node, most of the daughters leave and circulate around the body. When they encounter antigen, presented by macrophages and DC at the infection site, they secrete lymphokines.
►The most important lymphokine secreted by Th1 is interferon gamma (IFN-gamma ) which is pro-inflammatory, being chemotactic for blood monocytes and tissue macrophages. These cells move in large numbers into the area where the Th1 is recognizing antigen.
►They are also activated by IFN-gamma, becoming classically-activated M1 (or ‘angry’) macrophages which avidly ingest and kill bacteria or other foreign invaders.
-The macrophages release their own cytokines that intensify inflammation including tumor-necrosis factor alpha (TNFα) and IL -1.
–> Th1 also secrete IL -2 , which helps CTL (killer T cells) get fully activated after they recognize antige.
What citokine is responsible for producing fever during inflammation?
IL-1 is the main cause: in the pre-optic anterior hypothalamus, it stimulates the formation of PGE2, which slows the firing rate of certain temperature-control neurons to what they would normally do at, say 35°C.
->This activates the heat generation response (e.g., shivering,) producing fever.
Th17 Cells
How is its function similar to that of Th1?
It is useful in elimination of particularly difficult what?
What its effect if its response becomes chronic?
There is a newly-described, intensely-researched Th subset called Th17 because it makes the inflammatory lymphokine IL - 17 among others.
-It resembles the Th1 in that its main job seems to be causing inflammation; not surprisingly, then, it has been implicated in several autoimmune diseases, as has the Th1. It must do something useful for a living, of course; and that is resistance to particularly difficult bacterial and yeast pathogens.
It is helpful to think of Th1 and Th17 as pro-inflammatory, leading to the accumulation of classically activated M1 macrophages at the site of infection; the tactic is a vigorous response to get dangerous pathogens under control quickly. This is highly desirable, but also can get out of control; and if it becomes chronic can result in significant tissue damage.
Citokines, lymphokines and chemokines: What is their difference? or similarities?
Th2 cells
What lymphokines do these cells produce?
What cells do they activate?
Macrophages activated by Th2 cells are called? Are involved mainly in?
Which of the lymphokines is also a chemotactic agent for eosinohils?
In terms of response time, which cells Th1 or Th2 apper first or later?
Activated Th2 cells leave the lymph node as do Th1, and circulate through blood and lymph until they encounter their antigen again in the tissues.
Here the IL-4 , IL-5 and IL-13 they make attracts and activates macrophages, but in a different way than IFNγ does.
How? ►such macrophages are called alternatively activated or M2 , and are more involved in healing (debris removal, scar formation, walling off pathogens that M1 macrophages have failed to kill ).
►**IL-4 is also chemotactic for eosinophils, cells specialized for killing parasites like protozoans and worms.
►So Th1 are the cells of active, urgent destruction of invaders, via the M1 cells they stimulate; Th2 cells, which tend to appear later in sites of inflammation, are involved via M2 cells in repair and healing. As the yin and yang of T cell immunity they are an awesome pair.
Follicular Helper T cells (Tfh)
Where do they migrate after the arrival of DC to the lymph node?
What cells do they help in activating?
In isotype swithing of B cells, Tfh in the gut swith B cells from to main _____. What about in the spleen?
If no Tfh were made, what would be the only antibody that B cells could make?
Soon after the arrival of antigen-presenting DC in the lymph node, some activated Th cells can be seen migrating into the follicles of the cortex, where B cells are abundant. These are referred to as follicular helpers,
►Their role is to help B cells that have recognized antigen become activated and differentiate into antibody-secreting plasma cells. Tfh secrete a variety of cytokines, and by direct contact they stimulate the B cells to switch from secreting IgM, to IgG, IgA, or IgE. They tend to be heterogeneous; the Tfh in the gut, for example, switch B cells preferentially to IgA; those in spleen switch B cells to IgG.
The existence of Tfh reminds us that the antibody you make (or don ’t make) may be as much a read - out of T cell function as of B cells. If Tfh cells can’t communicate correctly with B cells, for example, you will have difficulty making any antibody class downstream from IgM.
Follicular helper T cells (Tfh)
What marker allows Th1 and Th2 to go into the follicles as Tfh?
The Th1 and their related Tfh action is to?
The Th2 and their related Tfh would perform what function?
►Studies of Tfh point up the somewhat fluid identity of Th subsets.
It’s likely that some Th1 and Th2 cells acquire a surface marker (the chemokine receptor CXCR5) that allows them to go into the follicle as Tfh.
Th1 and their related Tfh would thus, orchestrate aggressive resistance through M1 macrophages (IFNγ), killer T cells (IL -2), and, as Tfh, help for the complement-activating antibody classes.
Th2 and their related Tfh would orchestrate healing, worm-killing, and walling-off via M2 macrophages, eosinophils that they attract directly, and help for IgE production which activates mast cells as part of the worm-defense program.
Regulatory T cells (Treg)
What is their job?
What markers do Treg have?
What special transcription factor do they require?
What lymphokines do they produce?
Do they need antigen to function?
A small but not minor population of cells (about 5% of all Th cells) has been identified whose main job is to suppress the activation and function of all other Th cells.
-Most regulatory T cells have the phenotype CD4+/CD25+ and require the transcription factor FoxP3.
Surface CD4 puts them in the helper family.
►They produce TGFβ and IL - 10.
They are very potent; one can suppress 1000 Th cells. Mice that lack Treg, or part of their signaling pathways, get autoimmunity, and so do rare people with a similar genetic defect. But even without a genetic problem inadequate Treg function is common and leads to overactive immune responses and self- reactivity. We’ll discuss this more when we consider autoimmunity, inflammatory diseases, and regulation.
► Although Treg respond specifically to their corresponding antigen, their suppression of other T cells is not antigen-specific; any nearby Th is suppressed.
Cytotoxic (Killer) T cells
What are the two ways that a CTL can signal a cel to undergo apoptosis?
Where and who activated them?
Th1 ones helps activation of CTL by releasing what? For conversion into memory cells?
The phenomenon is quite wonderful. Immunize a person against a virus. Take some T cells from that person’s blood, and mix them with some of her cells that you’ve infected with the same virus in a test tube. Watch under the microscope: a T cell bumps into an infected cell, binds, and moves away after a few minutes. The ‘target’ cell looks fine but if you look inside it you see that its nucleus has collapsed in on itself and its DNA is fragmented. About an hour later, the cell disintegrates (lyses) if it hasn’t already been eaten by a phagocyte. In the few minutes of CTL-target contact, the killer gives the target the ‘kiss of death’ or lethal hit . It has signaled the target to commit suicide by activating a physiological cell death process (called apoptosis ) that leads to rapid DNA fragmentation and nuclear collapse (this would be useful in preventing virus replication).
There are two ways a CTL can signal a cell to undergo apoptosis.
1- It can engage the ‘death receptor’ Fas (CD95) on the target (CTLs bear the Fas ligand, CD95L). Crosslinked Fas activates a latent apoptosis pathway.
2-Or it can secrete the contents of certain ‘lytic granules’ which contain
proteases called granzymes, and other proteins called perforins which seem to allow the penetration of the granzymes into the target cell. These proteases trigger apoptosis.
CTL are activated in the lymph nodes after contact with an antigen-bearing DC. They also require, for activation, help from Th1 in the form of IL -2, and for conversion into memory cells, IL -21 , and probably other factors.
Memory cells
After a response to antigen with its rapid expansion of the relevant T cell clones, the number of T cells quickly declines, until perhaps 5% of the maximum amount are left a few weeks after infection or immunization.
–>These are memory cells, which can replace themselves, and be ready to rapidly differentiate into effector (helper, killer) cells when re- exposed to low antigen concentrations. There are surface markers for memory cells; their measurement is still mostly a research tool. Some memory cells circulate; other stay in the relevant tissue (‘tissue resident memory cells’) where they can respond rapidly.
Subpopulation markers to distinguish between B and T cells?
The surface marker________ distinguised B cells.
The ___2____ marker in on all T cells.
The ___3___ marker is on T helper cells
The __4__ marker is on CTL.
Can you distinguish between Th1 and Th2 based on surface antigen?
1- B cells are distinguished using antibodies to immunoglobulins or their chains, or to the surface marker CD20.
2- The most useful molecules on T cells are CD3, CD4, and CD8. CD stands for “cluster of differentiation ”, though I am not sure what that means.
► CD3 is on the surface of virtually all T cells.
–> CD4 is on T helpers
–> CD8 is on CTL.
There are no reliable surface antigens to distinguish Th1 from Th2; you have to look at the lymphokines they make.
T cells recognition is restricted to antigens in?
T cells are antigen-specific and ________.
they are restricted in their recognition of antigen, to antigen on the surface of cells (here, the target cells) genetically identical to themselves. That is, they do not “see” antigen alone, but only antigen presented to them on the surface of a genetically-identical cell.
In other words,
The T cell and the antigen-presenting cell must come from individuals who share alleles at a group of loci collectively called MHC (for Major Histocompatibility Complex), which code for surface glycoprotein molecules.
►Another way of sayin g this is that the T cell is antigen-specific and MHC -restricted. MHC antigens are very variable, that is, there are thousands of alleles in any population. The chances of yours being exactly the same as mine (or A’s the same as B’s) are extremely small.
Antigen presention to T cells:
Why is it an extrinsic pathway?
APC, and the mechanism the extrinsic pathway because it involves antigen from outside the APC.
Dendritic cells are the best at this. It’s this MHC- antigen complex that is presented to the receptor of an appropriate helper T cell.
T cells focus their attention into the cell’s _______.
In the structure of the MCH, the groove’s base is a _______ chain, and the two sides are ______ chains.
surfaces and do NOT interact with free antigens
T cell receptor (TCR)
what are the two chaisn of the TCR called?
What genes are used by TCR to make its receptors? Are they the same as those used by B cells?
How is recombination different from that of B cells?
How many CDRs do they have?
Both alpha and beta chains have________ domains.
The T cell receptor for antigen (TCR) is structurally reminiscent of antibody, and sequence data indicate a common ancestral gene.
The two chains are called alpha and beta (don’t confuse these with the α and β of Class II MHC), and each has a constant and a variable portion.
The T cell makes its receptor out of V, (D) and J regions — T cell genes, not the ones B cells use —recombined as in B cells, and like antibody,
►each chain has 3 CDRs 3 ; the process takes place in the thymus.
Both alpha and beta chains have transmembrane domains, unlike surface Ig, in which only the heavy chains are transmembrane:
Alpha chains are made from V and J segments; beta from V, D, and J (and so are more diverse than alphas.)
How TCR is activated?
What is the function of CD3?
What are the 3 signals for activation of a T cell?
What biochemical events happen after the T cell is stimulates?
-B7 in APC bins to CD28 in T cell to stimulate activation
-B7 binds to CTLA4 in T cell to inhibit activation
Intimately associated with the TCR is a complex of molecules called CD3 ; it has at least 5 chains.
It serves to transduce TCR signals for the T cell. This means that when a T cell binds the correct antigen + MHC with its TCR, the actual signal that turns the T cell on is transmitted by CD3.
This complexity implies a process that needs to be carefully controlled. When a Th cell binds to a good APC like a dendritic cell, it receives three sorts of signals.
1- The first is via its TCR — called the TCR-pMHC interaction (p meaning the antigenic peptide.)
2- The second are between an array of accessory molecular interactions which can only be provided by true APC, and that modify, enhance, or diminish activation.
3-The third involves a variety of cytokines that the APC may secrete to activate, inhibit, or modulate activation of the T cell.
Biochemical events follow that are typical of cells being stimulated: a rise in intracellular calcium, breakdown of membrane phospholipids, and activation of protein kinases which in turn activate transcription factors. Cytokine receptors are upregulated. The cell goes into cycle (proliferation) and begins to secrete lymphokines (differentiation). When the Th is a Th0, these interactions determine its differentiated phenotype.
T cells helping in the activation of B cells
For protein antigens a vigorous class-switched antibody response requires help from T cells, as we have mentioned previously.
How does a Tfh cell help a B cell get activated and make antibody?
Four experimental observations gave us the clues:
1- The T cell and the B cell must come from donors with the same MHC Class II.
2- The T cell and the B cell are not specific for the same epitope, but the epitopes they are specific for must both be on the same antigen molecule.
3- If you block the B cell’s ability to endocytose it cannot be helped by a T cell or make antibody.
4- The Tfh must contact the B cell.
What are lectins? Mitogens?
Give some examples:
How are they useful?
Summary of antigen presentation
