immuno lect 6

innate immune cells can only recognize

pathogens bearing surface molecules that are common to many pathogens and conserved over evolution

microorganisms evolve faster than the

hosts they infect

microorganisms often develop ways to

evade the innate cells

antigen receptors of B and T cells bind

specific protein or peptide antiens

when specific antigen is bound, the cell is

activated, proliferating, differentiating

each lymphocyte bears antigen receptor

of a single specificity

lymphocyte functions are

tailored responses based on environmental signals

3 examples of tailored lymphocyte fxns

different types of T helper effector cells, cytotoxic T cells, different types of antibodies

TCRs are

transmembrane heterodimers composed of either an alpha and a beta chain or a gamma or delta chain

extracellular variable regions contain

the antigen binding region

a functional TCR is in a complex with 4

transmembrane polypeptides collectively called CD3

CD3 help transduce

signals to activate the T cell

CD3 is not a

receptor, it does not bind ligand but is essential for intracellular signaling

CD4 binds to

MHC class 2 on antigen-presenting cell

CD8 binds to

MHC class 1 on antigen-presenting cell

unique genetic mechanism that only occurs inside

T and B lymphocytes during their development

random rearrangement of germline segments of the genes encoding

TCR

process requires protein complexes including the enzymes

RAG1 and RAG2 (recombination activating genes 1 and 2)

beta-chain genes are rearranged by

random joining of segments (D, J)

the new DJ segment is linked with a

V segment, making a new VDJ segment

alpha-chain genes are rearranged by

random joining of segments (V, J), making a new VJ segment

during the rearrangement of TCR genes, random nucleotides are

removed or added btwn the segments

combinatorial diversity is from the

random joining of different gene segments

junctional diversity is from

random nucleotides being removed or added btwn segments

junctional diversity is intentionally

sloppy ligation

example of junctional diversity

non-homologous DNA end joining

in non-homologous DNA end joining, the enzymes doing the work

are not critical

defective V(D)J recombination results in

profound immunodeficiencies

defective V(D)J recombination is either

naturally occurring or engineered

severe combined immunodeficiency is aka

SCID

severe combined immunodeficiency (SCID) is caused by 2 defects

DNA-PKcs defects and RAG deficiencies/defects

Which dog breed gets SCID, and from what defect?

Jack Russell Terrier; DNA-PKcs

Which horse breed gets SCID, and from what defect?

arabian horse, DNA-PKcs

How many possible TCRs can rearrangement produce?

10²⁰–10⁶¹

How many distinct naïve TCRs remain after selection?

About 10⁸

About how many genes does the human genome contain?

About 21,000, though many make multiple proteins and there are thousands of non-coding RNA genes

germline arrangement of the TCR gene contains

multiple segments

segments that are semi-randomly rearranged are called

combinatorial diversity

additional diversity that occurs when random nucleotides are added/deleted at the joining of segments is called

junctional diversity

TCR rearrangement is independent of

the antigen

early double-negative thymocytes express what marker

CD25

How many tries does a thymocyte get for TCRβ expression?

4

What is pre-Tα?

surrogate TCRa chain

when a functional alpha chain is produced that pairs efficiently with the beta chain,

CD3, CD4, CD8 thymocyte is ready to undergo selection

4 types of random mutation

nonsense, non-functional TCRs, self-reactive TCRs, non-self reactive TCRs

non-functional TCRs are

useless

self-reactive TCRs are

dangerous

non-self reactive TCRs are

good guys

after rearrangement, thymocytes express their

TCRs on their cell surface in complex w/CD3 and w/both CD4 and CD8, making double positive (DP) t cells

DP thymocytes interact w/

cortical thymic epithelial cells that express both MHC 1 and MHC2

cells that can interact w/MHC-peptide complexes are given

survival signals and live

cells that do not interact w/MHC-peptide complexes

die by apoptosis

DP thymocytes that bind well with MHC 1 lose

CD4 expression and become CD8 T cells

DP thymocytes that bind well with MHC 2 lose

CD8 expression and become CD4 t cells

positive selection determines

CD4 or CD8 expression and eliminates non-functional TCRs

medullary thymic epithelial cells are able to express

many proteins usually found in other tissues in the body

APCs in the medulla present

peptides from these many proteins

if the thymocyte binds too well, it will be

negatively selected and die

destruction of self-reactive thymocytes is called

central tolerance

negative selection eliminates

self-reactive TCRs

Very high affinity for self-peptide–MHC: outcome?

apoptosis, negative selection, removing self-reactive T cells

Higher affinity for self-peptide–MHC: signaling and outcome?

Activation of IL-2Rα (CD25) and FOXP3; positive selection into Tregs

Lower affinity for self-peptide–MHC: outcome?

Positive selection into effector T cells (Teff)

Very low affinity for self-peptide–MHC: outcome?

No survival signals; apoptosis (“death by neglect”)

What is “death by neglect”?

Death of thymocytes with very low MHC affinity, which can’t survive without TCR signaling

T regulatory cells (Tregs) come from

a subset of self-reactive thymocytes survive and differentiate into T regulatory cells

Tregs are

immunosuppressive T cells that can help prevent autoimmune responses in the periphery

Tregs are a type of

peripheral tolerance

peripheral tolerance are mechanisms that take place

outside primary lymphoid organs that prevent immune responses against self or harmless materials like food or commensals

Tregs prevents

autoimmune diseases

How common are γδ T cells in most mammals?

A small fraction of T cells

In which species are γδ T cells the majority of T cells?

Ruminants and chickens

Do γδ T cells express CD4 or CD8?

no

Which TCR loci can a developing double-negative T cell rearrange first?

TCR β, γ, or δ

When does a thymocyte become a γδ T cell?

When γ and δ are rearranged before TCR β

Can a T cell express both γδ and αβ?

No. TCR δ is deleted when TCR α is rearranged

Do γδ T cells require MHC to recognize antigen?

No. They can recognize unprocessed antigen without MHC

Where are γδ T cells often found?

Associated with mucosa

Why is the γδ repertoire less diverse?

They have few V gene segments

What function do γδ T cells have?

Cytotoxic, similar to CD8⁺ T cells

lymphocyte maturation diversity is through

random gene rearrangement, selection

What 3 signals are needed for T cell proliferation and differentiation into effector and memory cells?

(1) Antigen, (2) co-stimulation, (3) cytokines

Where do naïve CD4 and CD8 T cells go after leaving the thymus?

They can migrate to lymph nodes

signal 1 can be activated only by an

APC presenting specific antigen

Where do T cell antigens come from?

Microbial proteins, tumor antigens

types of microbial proteins

bacteria, parasites, viruses

How are antigens presented to CD4⁺ T cells?

Extracellular antigens are endocytosed and presented on MHC II

How are antigens presented to CD8⁺ T cells?

Intracellular antigens from cytosolic proteins are presented on MHC I

What is cross-presentation

DCs take up extracellular antigens and present them to CD8⁺ T cells

Which molecules make up Signal 2?

CD80/86 on the APC interacting with CD28 on the T cell

What is another name for CD80/CD86?

B7

Where is CD80/86 expressed, and at what level?

Only on APCs, at low levels unless the APC is activated

What activates APCs to increase CD80/86?

Cytokines, pathogens, or T cells

Are CD80/86 and CD28 the only co-stimulatory molecules?

No. Others can also play a role.

What happens if a naïve T cell gets Signal 1 without Signal 2?

Apoptosis or anergy

What is anergy?

A state of non-responsiveness

Why is the need for Signal 2 important?

it’s another check that reduces self-reactivity and maintains peripheral tolerance

Where does Signal 3 come from?

Cytokines in the environment or produced by the APC

What does Signal 3 determine?

The phenotype (fate) of the T cell, such as Th1 or Th2, by providing context

What kind of IL-2 receptor do naïve T cells express?

A low-affinity version