Immun 2

structure of a TCR

heterodimer

made of alpha and beta chain

has immunoglobulin folds with disulfide bonds

TCR vs BCR

TCR is small and a heterodimer

BCR is 4 polypeptides coming together

alpha and beta region

each has a variable and constant region

variable determines binding specificity

traditional TCR

alpha and beta

nontraditional TCR

gamma and delta

TCR has a small

cytoplasmic tail

gamma and delta are found in

mucosal areas

gamma and delta T cells (general)

recognize lipids presented by CD1 molecules

first line defense (activate within hours of invasion of pathogens)

bridge between innate and adaptive

has different subsets

gamma and delta T cells abilities

secrete cytokines

cytotoxic effects

phagocytosis

can kill via diploid granules

form memory cells

(both adaptive and innate abilities)

gamma and delta do

VDJ recombination but not as variable as alpha and beta

only use a particilar v segment

people who have alot of gamma and delta t cells

have the V gamma 9 and the VD2 variable regions

CD3 molecule and zeta chain

help with intracellular signaling due to really short cytoplasmic tail

10 I 10 is involved

similar to IG alpha and beta on B cell

helps with activation

CD4 and CD8

co receptors

help binding from TCR

recognize sides of MHC2 and MHC1

ensures that TCR from a helper cell will not recognize the MHC 1 because CD4 can’t bind to MHC1

CD28

co stimulatory molecule for t cells

main molecule for activation

CD2

adhesion molecule

help in activation

serve as a cost inventory molecule

CTLA 4

involved in t cell deactivation

without it, overactivated t cells, cytokine overload

t cell deactivation

once it activates, it downregulated CD 28, and upregulates CTLA 4 to prevent it from continually dividing

CD 28 and CTLA 4 both binds to B7 on APC

B7

activating t cell is it has CD28

deactivated if the t cell has CTLA 4

CD40 ligand

b cell activation

CD 62L and CRR 7

homing receptors

guide naive t cell to go to lymph node

memory cells don’t have these molecules, they dont go to lymph nodes, they circulate looking for antigen

TCR diversity

alpha has VJ

goes through VDJ, allelic exclusion and junction diversity

combination between beta and alpha

TCR does NOT

go through a second round of improving

TCR express either

alpha and beta OR gamma and alpha

never both at the same time due to aletic exclusino

TCR rearrangement in order

beta or gamma

if beta rearranges then it becomes alpha beta

once alpha rearranges it deletes delta

if it rearranges delta then it will go back and rearrange to gamma

types of antigen

endogenous

exogenous

endogenous antigens

antigens within the cell

presented by MHC 1

recognized by t killer cells

exogenous antigens

outside of the cell

phagocytose or endocytose

presented on MHC2

recognized by t helper

cross presentation

endogenous antigen being presented on MHC 2 or exogenous antigen being presented on MHC 1

MHC discovery

scientist were doing transplantation of skin grafts between different strands of mice, there was a rejection pattern

hybrid accept grafts

the more diverse genetic background the mouse is the more likely to accept graph

t killer cells have

CD8

recognize and bind to the side of MHC1

t helper cells have

CD4

recognize and binds to the side of MHC 2

MHC1

beta 2 microglobulin loosely connected

has to fold properly

binding grove is on top

hand is in the cytoplasm

MHC2

dimer

alpha and beta

binding grove is on top

hand is membrane bound

both MHC have

3 loci

MHC 2 without peptide

needs a spacer to keep the shape of its folding

uses CLIP in the binding grove

when peptide comes, CLIP leaves

MHC 1 number of amino acids

likes to bind to peptide 9 amino acids long due to being more closed

MHC 2 number of amino acids

likes to bind to peptide with 13-18 amino acids due to being more open

MHC1 is in

all nucleated cells EXCEPT red blood cells

MHC2 is on

APCs- professional antigen presenting cells(DC, macrophage, b cells)

MHC1 process

is in the cytoplasm

antigen processed by protostomes that cut up peptide

pieces go to rough ER via TAP protein

MHC is synthesized in lumen of rough ER

selective peptide binds to grove

goes to cell membrane

The MHC1 and 2 process is

energy dependent

cross presentation is for

DC presenting viral antigens because DC are not infected by viruses

to not be infected but still be able to present virus on MHC 1 it uses this

cross presentation process

DC phagocytose virus and breaks it down, then presents on both MHC 1 and 2

class 2 presents to t helper

class 1 presents to t killer

CD 1

looks like MHC

holds lipids and presents it to special cells

presets it to natural killer t cells or gamma delta cells

gamma delta and natural killer t cells

recognize lipid antigens

NKT cell secretes cytokines (ACDD)

gamma delta do kill activities

super antigens

not presented by MHC

bind to MHC and TCR and force them to come together

triggers t cell activation

binds to side so not t cell specific

usually t helper, they secrete alot of cytokines because they are globally being activated

cytokine flood causes body to shut down, induce shock, blood pressure goes down, you faint and may die from shock

t cell positive selection

TCR that respond to self MHC are positively selected

cells that dont respond die

partner is thymic epithelia cells

t cell negative selection

t cell that reacts to self antigen get deleted

needs to bond weakly, if bond stong then dies

t cell development happens in the

thymus

when a t cell first arrived at the thymus

is double negative

double negative

t cell has neither CD4 nor CD8

also called pro t cells

t cell beta chain rearrangement

most early stage

beta chain BDJ recombination

successful rearrangement leads to a beta chain with surrogate pre alpha chain

alpha chain rearrangement

after beta chain rearrangement

if successful becomes double positive

double positive

has proper TCR

has beta chain

no proper alpha chain

pre t cell (only heavy chain)

mature t cell

down regulates from double positive to either single CD4 or CD8

positive selection happens in

cortex

negative selection happens in the

medulla region or closer to center of thymus

thymocytes

immature t cell

interact with DC, macrophages and epithelia cells

AIRE

gene

introduce expression of many antigens and many proteins

purpose is so that developing t cells can be selected against (negative selection)

allows these antigens from all over to be precent in the thymus

if a t cell binds to MHC 2

it needs to be CD4 positive

if a t cell binds to MCH 1

it needs to be CD8 positive

how to determine CD8 or CD4

downregulate CD8

if signal persists then it stays with CD4

if signal disappears then it downregulates CD4 and upregulates CD8

t cell graduation rate

1%

alloreactivity

1-5% of t cells that recognize self MHC are actually recognizing non self MHC plus foreign antigen or self antigen

foreign MCH can resemble self MHC when specific antigen is present

exists in graft rejection

graft versus host disease

bone marrow transplant that contains t cell and the t cells attack the recipient

mixed lymphocyte reaction

t cell from doner attack recipient t cells

indirect alloy reactivity

host t cell recognizes foreign MHC with peptide and kill foreign cell

t cell activation

CD3 needs to be engaged with MHC and peptide

CD4 or CD8 needs to be binded to MHC

co stimulatory molecule

after t cell recieves signals for activation

is does sigal transduction

signal is transmitted into cell to induce responce

signal 1

TCR signaling

signal 2

costimulatory molecule signaling-

CD40-CD40L

CD28

if signal 2 is missing and signal 1 is precent

t cell goes into anergic state

peripheral tolerance

DC maturation

immature DC grab antigen

phagocytosis antigen and present on MHC 2

upregulates B7 then becomes mature

migrates to lymph node

can mature in response to cytokines

immuno synapse

t cell and DC touching

immuno synaps inner circle

MHC, TCR

CD3, CD4/CD8

B7 binds to CD28

immuno synaps outer circle

adhesion molecules (CD2)

induce anergy

t cell interacts with immature APC (has no B7) or B7 is blocked by an antibody

perminant

t cell proliferation

upgrades CD 25 to IL2 (a high affinity cytokine receptor)

IL2 binds to IL2 receptor which says to keep making clones

types of t helper

t helper 1

t helper 2

t helper 17

t reg

each have differnt cytokines

t helper 1

activated macrophages

needs IL12

secretes IL2 and IFNy

t helper 2

induce allergic reactions(eosinophiles) or reaction against worms

needs IL4

secretes IL4,5 and 13

t helper 17

activate neutrophils, epithelial cells, promote inflammation

in mucosal area

need IL21

secrete IL17,22

t reg

anti-inflammatory, keep other cells in check

need TGFb

secrete TGFb and IL10

express FOXp3 as transcription factor

t helper negatively regulate each other pathway

T helper 2 secrete cytokine that suppress the differentiation into T helper 1

T helper 1 and 2 inbalence

if T helper 2 is higher than t helper 1 then can get allergy and asthma/autoimmune reactions

central t reg

made in thymus

dont needs to see antigen

immature DC

dont express Co stimulator receptors

no B7

t killer and DC

MHC1 bearing peptide that TCR is specific for

cost irrigation molecule

cytokines

How DC become mature

toll like receptors engage with pathogen and recognize it

effactor t cell also called

CTL

t helper independent

does not lead to memory t killer cells

no t helpers involved to activate t killer

t helper dependent

t killer needs t helper

T helper, DC (mature or immature) and T killer all next to each other called the 3 cell model

t helper licensed DC though CD40-CD40 ligand

once DC is licensed then it activates t killer

how t killer kils

recognize MHC class 1 bearing specific peptide that it recognizes

secretes perforin and granzyme B

induce apoptosis

perforin

makes hole for granzyme to go in

granzyme

enzyme that cleavages different proteins

protease that activates caspase

caspases

involved in apoptosis

activated by cleavage

cell apoptosis via granzyme B

caspases activates

cleave downstream other caspases

cell starts blabbing-forming vascicles

DNA gets chopped up, cell membrane and protein is chopped up

whole cell gets phagocyte

fast - fast ligand

t cell upgrade the fast ligand

allows other cells to kill them

without leads to autoimmunity

memory cells

central memory and effector memory

central memory

long term memory cells

stay in lymph node