Answer to: What happens after a macrophage engulfs a pathogen and Th response?

[TrueLight]

i got that question from someone but i would like to post it here for you to see...

hmm lol there is quite a lot to explain...

okay first of all Helper T cells and Cytotoxic T cells are already differentiated when they leave the thymus after development. These cells circulate around the body, via the blood and via the lymphatics (go through lymphatics empty into blood circulate around and around until they encounter antigen or die if they don’t). Also an adaptive immune response is initiated in the peripheral lymphoid organs (ie: lymph nodes, spleen, mucosa associated lymphoid tissue). You cannot get one initiated out in the body (well its very 99.999% my guess unlikely) just because the chance of one t or b cell encountering its specific antigen is very slim and also for the t cell to be activated you need co-simulation and this requires a tight connection between a T cell and a antigen presenting cell and when the blood is whooshing past very fast its hardly going to happen. So to solve this problem pathogens that invade anywhere in the body can have a greatly increased chance of meeting a T cell that binds to its antigen by meeting in the peripheral lymphoid organs. This provides a meeting place for the dendritic cell and a T cell and B cell to meet its ‘cognate’ antigen.

Okay so the other point to make is that dendritic cells (an APC) are the major APC, the primary APC to actually initiate the first activation of T cells. It’s the most important one in presenting antigen to recirculating naive T cells. It overwhelmingly drives the initial clonal expansion and differentiation of naive T cells into effector T cells. Macrophages are usually pretty stationary just crawling across the surface, but dendritic cells really have the migratory function to move to the nearest lymph node or lymphoid organ once they encounter a PAMP and engulf it. Although macrophages do ingest pathogens and do present them on their MHC molecules, they mainly interact with already primed T cells.  Although bacteria and virus particles can travel through the lymph by themselves and thus can end up in a lymph node for example and be captured by dendritic cells there too. Okay so let’s say a dendritic cell has migrated to the lymph node carrying a pathogen antigen on its MHC marker... If the dendritic cell had engulfed it into a vesicle it would present and load it onto MHC2 (CD4 T cells can only bind to MHC2), if the dendritic cell was infected with a virus that is in its cytoplasm , it would present it to MHC 1 (CD8 T cells can only bind to MHC1)... although you can get cross presenting when viruses can’t infect dendritic cells (although don’t worry about this)... So the dendritic cell is in the lymph node, great ... now there would be heaps of T cells scanning quickly over the dendritic cell to see if its T cell receptor can bind to the peptide presented by the dendritic cell... if one T cell happens to bind to it, it stops migrating, it sticks onto it... now that the CD4 T cell receptor and the MHC 2/peptide is engaged (for example) other receptors are needed to activate a naive T cell... There really are 3 signals that activate a naive T cell... 1. T cell receptor (TCR) binding to its MHC/cognate antigen. 2. Co stimulatory molecules (that tell it it really is a danger and needs to respond). 3. Cytokines (for proliferation and also in terms of helper T cell for differentiation into Th1, Th2, Th17)....Dendritic cells that arrive in the lymph node (for e.g.) arrive matured, although when they are in the periphery they are in an immature state where they don’t express co stimulatory molecules on their surface... but when matured express lots of co stimulatory molecules and adhesion molecules and MHC.  So once dendritic cells MHC/peptide and TCR and also co stimulatory molecules bind, adhesion molecules stabilise the two very close together. A signal is passed through the T cell receptor that activates it, promotes its survival, proliferation and differentiation into its effector form (whether that’s cytotoxic t cells, Th1, Th2 or Th17 cells)... This signal also induces the up regulation by the T cell to create IL-2 (a cytokine that causes proliferation of itself)... Oh i also forgot about signal 3 (which comes from the APC that activates the naive T cell- important for differentiation)... naive CD4 T cells become Th1 (important for bacterial infections and promote activation of macrophages) when interferon-gamma and IL-12 is produced... naive CD4 T Cells becomes Th2  (important for parasites and allergens) in the presence of IL-4 etc etc...   

Okay so once the (eg) naive CD4 T cell is activated, it proliferates, it differentiates, it goes out of the lymph node back into the blood and travels to the site of infection.... CD4 effector T cells (helper t cells) help activate macrophages and induce B cells to secrete antibody particularly IgG when Th1 secrete IFN-gamma and IgE when Th2 secrete IL-4... by secreting cytokines that help do this (Th1 secrete IFN-gamma, TNF-a, IL-3 etc)... so they go out to site of infection find their ‘cognate’ antigen on the MHC 2 (if helper t cells) and secrete those cytokines.. CD8 cytotoxic t cells secrete interferon gamma and TNF-a too as well as target cells that have their cognate antigen on MHC 1 for destruction... 

Just on macrophages, i haven’t really talked about them because they aren’t that important in initiation the primary adaptive immune response..... macrophages ingest pathogens... if the macrophage fails to kill a pathogen it has ingested (eg : by inhibiting fusion of lysosomes to the phagosomes)... it needs helps doing so and it gets this help from Th1 (T helper type 1 cells) cells. These Th1 cells are able to secrete cytokines (IFN-gamma) that really enhances the microbicidal activities of the macrophage, thus hopefully enabling the macrophage to kill the pathogen.... also i said earlier that macrophages are probably more important after the naive T cell has been activated or primed and out in the periphery... these activated T cells that i said come out of the lymph node or spleen etc.. need to be restimulated by the antigen it originally got stimulated by... this is where macrophages that display the antigen on their MHC can present it to these activated T cells and continually “pump” them up so they are stimulated..

Here’s a quote from the textbook

“At present, there is very little evidence that macrophages ever initiate T-cell immunity, so it is likely that their expression of co-stimulatory molecules is more important for expanding primary or secondary responses already initiated by dendritic cells. This might be envisaged to be important for effector or memory T cells that enter the site of infection.” 
     
So yeah... don’t know why your teachers keep telling you about macrophages and ignore or mention little about dendritic cells...

Anyway if you managed to read through all that and i confused you... haha sorry ... just ask if any part if unclear

[TrueLight]

Another question and answer and i'll post it up here for people to see

How does the immune system distinguish 'self' from 'nonself'?

MHC molecules or MHC proteins are encoded by MHC (actually in humans they are called HLA) genes.

Or you can say MHC proteins are encoded by the MHC (a region of a chromosome that includes a ‘complex’ of genes involved in antigen presentation).

The proteins produced by those genes are called MHC molecules or proteins that eventually end up on the cell surface.

MHC1 are found on all nucleated cells (is RBC the only cell to have no nucleus? Probably)

MHC2 are found on professional antigen presenting cells (you can exclude professional)... dendritic cells, macrophages and B cells...



Basically all B and T cells when they mature and start making their receptors can make a vast array of receptors that can bind anything, it’s random. See B and T cells don’t have receptors magically that know to respond to a pathogen... These receptors can bind to our own proteins or whatever. The thing that happens though is that T cells that mature in the thymus undergo positive and negative selection where only the T cell that recognise “self” MHC bound to self peptide are selected to survive. Negative selection also occurs but this involves the strength of the interaction where if the T cell receptor binds too strongly to self MHC/self peptide, it is induced to die... so you see in the end most T cell receptors that can bind self antigens strongly and thus potentially auto reactive, die and the thus the T cells left (around 3% make it past this test) recognise the other peptides that are potentially on pathogens... So T cells becomes “tolerized” to self antigens, they don’t react to it. There are also other tolerance mechanisms in the periphery if any auto reactive T cell escapes that prevents them from reacting to self antigen... B cells also undergo this positive and negative selection (its more about negative selection though since b cells already encode mhc) in the bone marrow when they develop where those that recognise self antigen are killed (negative selection)  and the ones that don’t are released and B cells are selected positively for expression of intact receptors...

So in the end the receptors they have don’t recognise self peptides or if they do they can become anergized (anyway this is a peripheral tolerance mechanism)...

The whole thing with MHC is that because your own B and T cells do not react to self MHC and T cells are self-MHC restricted... so those cells have been allowed to leave the bone marrow or thymus and its receptors have the ability to recognise self MHC... although when foreign MHC comes in like transplant, it is recognised as “non” self because it’s a completely different molecule then what the T cell recognized in development and became tolerized to... although it may have the same general structure, a few amino changes here and there and its completely different....

Hmm i recommend googling: central tolerance and peripheral tolerance... and you’ll see what i’m talking about if you don’t understand...lol i hope im not confusing things more

T cell development
http://www.youtube.com/watch?v=odLLr6mjaUQ

[lexitu]

First of all, thanks a lot for your help both here and on Douchy's forum ( .

Just a quick one - I was wondering whether Th cells also have specific receptors when they assist B cells? Or can any Th cell assist a B cell?

[TrueLight]

Thats okay

no the helper t cell help is antigen specific

B cells that bind an antigen, internalize it (remember B cells are antigen presenting cells) and process it and display the antigen fragments onto MHC 2. Now remember that CD4 T cells can only recognise peptide in context of MHC.... so now B cells that are displaying peptide on MHC can be recognised by helper t cells... [now only effector helper T cells can activate B cells so you see dendritic cells need to activate the naive CD4 t cells first]... So the T cell receptor is specific for that antigen on the surface of the B cells MHC... once they bind CD40 ligand is upregulated onto T cells and bind to CD40 on B cells which induces a signal that tells it to proliferate, produce antibodies and mature etc... cytokines are also released to tell the B cell to proliferate even more and produce more immunoglobulins.. and undergo class switching etc..

but yeah so helper t cell is antigen specific to what the B cell processed and presented on its mhc...

now you can also get B cells activated by (what they term thymus independent antigens) by binding of microbial sugar etc... or by lots of crosslinking of b cell receptors to antigen...

now the whole thing where the b cell and t cell come together and other things... i don't think is important for you now.. but if your confused with anything just ask

[lexitu]

Okay thanks a lot for that. At first this stuff is sort of incomprehensible just because it is so unbelievably precise and so many different cells and molecules are involved.

[TrueLight]

tell me about it

once you start getting even more specific it gets even more complicated... lol

[monokekie]

Thank you TrueLight

[TrueLight]

heres a review to antibody response to virus

Antibodies, viruses and vaccines
Dennis R. Burton

[TrueLight]

going to bump because i think this might be useful now