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Chap 8-Oct 25th 2012 T cell developlment Positive selection-can you recognize antigen presented on self-MHC Negative selection-Do

you recognize self, are you self-reactive T cell has to also make certain decisionsam I going to be a gamma delta t cells or an alpha beta t cell. T cell also has to decide if CD4 or CD8 if alpha beta. There are some T cells that have neither CD4 or CD8

Thymus Has two sections cortex and medulla. Both sections have epithelial cells that do different things. It is the interaction with B cells that help with the positive and negative selection Mice are born with very immature thymusif you take a newborn mouse and steal their thymus..they have very few functional T cellsturns out there are a few sites where a couple T cells can mature. Cortex more dense staining than medulla Thymocytes (developing thymus cells) are in contact with developing epithelial cells a lot of cross communication how positive and negative selection happen

Flow cytometry If you take antibody and tagged with floures. Mix them with cellsCells will then be tagged

Double negative-have neither CD4 nor CD8. Ones that are going to become alpha beta get to be double positive Different things happen in different parts of the thymus.

How does it decide alpha beta vs gamma delta.

Once you make alpha chain you delete delta.

It is a race to see who can make surface receptor firstERK sends signals to turn off the other.You become committed to a specific one. In fetuses you actually get more gamma deltas than alpha betas. Pre TCR doesnt need a ligand to signal just needs to get up to surface and associate with CD3..get signal to send. Beta chain has more than oneso you can have several tries with beta.you have duplications of Beta..more chance of forming successful beta chain

During early development, you are making mostly gamma delta.They come in waveseach wave has a particular v gamma and a particular delta chain too There are some NKT cells which need lipids presented to them in a non classical MHC Dendritic epithelial T cellsoccupy your skinact as sentinels.they see human delta 2 cellssees an intermediate in synthesis of greasy compundsturpines that bacteria makeintermediate made by a lot of bacteria. Bacteria that dont make that particular intermediate e.g. staphdont activate those . Kind of like an innate receptor gene encoded. When you rearrange alpha, you delete delta

Alpha and beta both have a lot of n nucleotide addition Why dont you get a mixed type of receptorthey just dont fit well together. Rare that you get a b cell with different BCRs.but like a third of t cells have different TCRs. Generally have same beta chain but different alpha chain Why doesnt this matter Because of the way a positive and negative selection work and TCR function it is unlikely that both receptors will function. Self MHC + foreign peptide-altered self Positive selection (DO or die)-can TCR interact with peptide borne by self MHC. If it cant, double positive will die by neglect within 3 days in thymus. Negative selection (Do and die) -Get rid of those that interact with self on self MHC.

Why are T cells restricted to your self-MHC if they dont recognize self they will flunk positive selection. Why dont you clobber yourself with T cells-all those that would die in negative selection.

How do Positive and Negative Selection work Its not what genes the bone cell marrow have its what thymus they matured in ..you are your thymus. Have both MHC a and b on the surface , codominant, but restricted to MHC a, but get rid of TCR...TCR has nothing to do with whats on its surface, It doesnt look for whats on its surface looks for what its TCR recognizes. What you have on your surface is not what you are. MHC restriction depends on TCR not on what you are/on your surface What your T cells think of as self is haplotype of your thymus Thymus declines with age

If you interact with an MHC 1, you become a CD8, if you interact with an MHC2 you become a CD4 Flunked positive selection, never saw MHC molecule that they recognized. Certain v regions have affinity for certain MHC alleles, remember CDR1 AND 2 react largely with MHC and not with peptide

Use antibodies as fake ligands Two types of antibodies -Agonist-if it binds antibody and thinks its engage dits ligand -Antagonist-just blocked it

Have organ cultureshas develpopn g thymocytesmouse is double negative for MHC 1- AND mhc2-no MHC molecules in surface of thymic epithelium. They will die if they cant find MHC .flunk positive selection. We can fool thymocytes into thinking that they have found MHC complexwhen they find MHC , TCRS GET engaged and CD4 or CD8we can fool it into thinking that it is engaged by giving it antibodieswe can have for eg anti cd8 and anti tcrt cell can say aha theyve both been engaged ive passes positive selection Antibodies can sometimes substitute for ligand. Some antibodies are agonistsones that mimic ligand that receptor usually grabs onto. Antagonist is one that engages ligand in such a way that it doesnt signal and blocks real ligand from binding. The t cells that mature under this condition are restricted to an MHC totally randomsince they didnt actually see an MHC. Its also inherentits not like we make TCR that are garbage. CDR 1 AND cdr 2 are germline and interact with MHC. SO all of TCRs would fit with some MHC molecule. Each one restricted to a particular MHC even though it wasnt actually activated by one.

How does a t cell decide if it is going to be CD8 or CD4? Depends on TCR. Its TCR recognizes If youre a T cell and you have that recognizes/sees only class one, ou will still be double positive If you have a TCR that sees MHC1, you will eventually only have CD8.

Positive selection happens on/by interacting with cortical thymic epithelial cellsno need to express it on other cells of body. CD4 interacts with constant parts of MHC molecule. You need to engage both the TCR and the CD4 in order to rescue developing thymocyte with positive selection. Positive selection involves binding to MHC on thymic cortical eoithelisal cells and the engagement of its co-receptor with MHC on thymic epithelial cells Thymic has to engage with both TCR and MHC for positive selection.

What triggers negative selection When a developing T cell sees an MHC peptide complex that would activate it, it dies. Tunnel method You can look at apoptotic cells and label them. Male specific peptide called HY Hy is on surface of basically all male cells, it can cause 100% skin rejection from male to female in mice. It also leads to graft vs host.

How can you detect T cells that have TCR specific to something

Negative selection happens in thymusyour thymus makes certain proteins but it doesnt make all the ones for example like the ones in liver. So how do you negatively select against thigns that arent in your thymus? Through a molecule called AIRE. The medullary thymic epithelial cells express a TF called AIRE (Auto immune response). SOME OF THEM EXPRESS IT. AIRE leads to ectopic (not in its right place/promiscuous ) peripheral expression of They are able to present these self antigens to developing t cells for negative selection. This is call shadow self-the self being presented by mTECscTECs dont do it. This is why you dont clobber your own organs with your t cells. There are some people who lack AIRE and these people have a certain disease. mTECS are expressed by some dendritic cells and some lymphoid oneswe are not sure why as yet. It expresses these antigenschops them up and presents them on MHC 1 and 2. How efficient is negative selction-central tolerance Pretty good but not perfect. There are some mechanisms of peripheral tolerance. E.g. if you present a self antigen to a t cell but doesnt get signal 2, the t cell is shut off. If they see a self-antigen in the context of inflammation, however you can get a reaction to self.

What cells besides mTecs participate in negative selection Some cells from the bone marrow are able to negatively select t cells that would clobber b. It must be that some bone marrow cells participate in negative selection. Bone marrow cells are enough to be able to negatively select cells

T cells are negatively selected on three different kinds of cells mTECS Dendritic cells and or Macrophages present in thymus Otherwise why is the mouse accepting the transplant. Mice have to be congenic which means they can only differ in MHC alleles for the experiment to work.

The paradox If we kill T cells that dont see self-peptide MHC (THAT DONT PASS postivive selection) and we kill T cells that do why do we have any t cells left. There must be a difference in the way we positively select and the way we negatively select.

Is there anything funny about way cTECs(ones tht do positive selection) process antigen? Yeah they do a lot of autophagy and instead of using cathepsin s, they use a different cathephsin l. The path of degradation a bit different because they use different peptides How are peptides prepared for MHC 1prepared through proteasome. There are really three kinds of proteasomes Thymoproteosome-has a special subunit if beta 5 called t and because if that peptides that are beign made in cTECS are different than those made anywhere else. The ones that t cells encounter in positive selection are different than ones in peripheryso doesnt matter if T cells see it. Is it sort of like

Peptides presented on cTECs and mTECs different

CTEC presents on MHC 1 and 2 a completely different set of peptides than you will see elsewhere in the periphery.

mTECs dont have thymoproteosome they have regular ones.

Lymphocytes go where they go because of special chemokines. B cells die if they dont get actuvated in a week B cells we have been talking about are b2 b cells. B and T cells dont really divide in periphery Spleen filters your bloodsame way lymph nodes filter your lymph

There are peripheral mechanisms of tolerancenot just in the thymus. Why have anergized cells around?

How can