T Cells/TCRs/APCs - Sant'Angelo 4/4/16 Flashcards Preview

Immunity > T Cells/TCRs/APCs - Sant'Angelo 4/4/16 > Flashcards

Flashcards in T Cells/TCRs/APCs - Sant'Angelo 4/4/16 Deck (23):
1

 cells of innate immunity which also have adaptive immunity fx

professional phagocytes

  • macrophages
  • neutrophils (PMNs)

NK cells

dendritic cells : phagocytosis, antigen presentation, production of cytokines

  • antigen presenting (mDC)
  • interferen producing (pDC)

2

antigen presenting cells

initiators of adaptive immune response

collect proteins (many self, some pathogenic), break them down, present peptides to T cells

  • enables T cells to respond, if necessary → adaptive immune response

3

what happens when a naive T cell comes across an MHC-peptide complex that requires a response?

naive T cell → differentiation into effectors T cell and memory T cells

  • effector T cells: produce effector molecules like cytokines (IL4, IFn gamma, etc)
    • stick around for a while (like antibodies), contribute to "protective immunity"
  • memory T cells: long-lived, antigen-specific, able to generate rapid response on reexposure
    • contribute to "immunological memory"

4

clonal selection hypothesis

lymphocytes mature in lymphoid organs (bone marrow or thymus) in the absence of antigens

clones of mature lymphocytes (each specific for single antigen - collectively specific for diverse selection of antigens) enter lymphoid tissues, where they'll encounter antigens presented by APCs

  • antigen specific clones are selected/activated by antigens → antigen specific immune response occurs!

5

T cell recognition of MHC-peptide complex

TCR recognizes both

  • contact residue of peptide
  • polymorphic residue of MHC

recall: MHC selectively binds peptides based on their anchor residues in "pockets"

6

costimulation of T cells

 

link to innate immune response

important role in....__________

T cells must receive 2 signals in order to be fully activated

 

1. TCR binds to to antigen-HLA complex on the DC or APC → signal 1, primes T cell for activation and expansion once..

2. CD28 binds to B7 molecules → costimulatory signal, signal 2 

naive CD4/CD8 T cells require both to be activated

 

link to innate immunity

costimulatory molecules are upregulated on APCs in response to signals from the innate immune response

 

important role in TOLERANCE

"resting" APC is costimulator-deficient → no T cell response/anergy (fx unresponsiveness)

  • prevents autoimmunity!
  • in order to get the T cells going, you need the costimulator, which won't be seen unless the APCs are activated by infection or innate immunity → TOLERANCE

once APCs are activated by microbes and innate immune response → increased expression of costimulators (B7-CD28 interaction), secretion of cytokines (IL12)

  • leads to T cell survival, prolif, diff → effector and memory T cells!

 

7

consequences of inability to costimulate T cells

lack of costimulation → inhibition of T cell response

  • cancer: malignant tumors express tumor restricted antigen (TRA) but no costimm molecules → T cells can't be activated, even if specific for TRA (anergy) → tumor grows
  • makes tumors hard to clear

8

how do you turn off a T cell response?

T cell responses must be turned on (costimulation by signal1 TCR-antigen/HLA binding and by signal2 innate/infection→B7/CD28 binding) and also turned off

crosslinking of CD28 and subsequent activation of T cells leads to upreg production of CTLA-4 

  • CTLA-4 binds to B7 (more avidly than CD28) → shuts down T cell response, prob by multiple mechs

 

if you have an uncontrolled immune response (toxic shock syndrome), get massive production of cytokines - cytokine storm - which can be fatal

 

 

9

therapeutic costimulatory blockade

if a person has overactive T cells → aberrantly causing autoimmunity

introduce soluble version of CTLA-4 that's not bound to APC : CTLA-4 Ig

  • does what regular CTLA-4 would do, interrupts the abberant activation by blocking costimulation via signal2

thought: doesnt this shut down ALL T cell response? 

not as far as we can tell...

10

enhancing tumor immunity via blockade of CLTA-4 function

development of monoclonal antibody YERVOY that binds to CTLA-4, blocks its interaction with B7!

  • keeps T cell activated, potentiates anti-tumor response
  • typically though, also has some autoimmune effect :(

**note, B7 has 2 versions, B7.1=CD80, B72=CD86

 

big time application of YERVOY : life extension and/or cure of late stage melanoma patients for whom all other treatment options have failed

11

components of TCR complex: T cell activation

 

activation cascade

how do T cells stay associated with MHC long enough for all this to happen?

TCR is a heterodimer (alpha and beta chains) transmembrane protein BUT...its cytoplasmic regions do very little

→ there must be other players involved in the production/transduction of the signal that TCR binding generates into the cell

enter: complex of proteins collectively referred to as CD3 (2 pairs of epsilon and gamma chains; pair of zeta chains which interact directly with TCR)

  • CD3 has ITAMs (immunoreceptor Tyr-based activation motif)

 

as part of early signaling events in T cell activation, antigen recognition occurs → TCR complex and coreceptors cluster on a lipid raft

  • Lck (lympocyte-specific protein Tyr kinase) phosphorylates the Tyr residues in ITAMs
  • ZAP-70 (zeta-chain associated protein) binds to P-Tyr and P's adaptor proteins, such as LAT (linker for activation of T cells)
  • cascade which will ultimately change gene expression

 

T cells have relatively low affinity for MHC, so make use of various ligand-receptor pairs to stabilize interactions

  • LFA1 : ICAM1 [APCs, endothelium ligand]
  • VLA1 : VCAM1 [endothelium]
    • way into CNS! as in multiple sclerosis, destroying neurons

12

functional specialization among T cell subsets

essential for immune system fx

CD8 T cell : cytotoxic T cell, recognizes (mainly) viralpeptide-MHC I complex → kills infected cell

CD4 T cell : helper T cell

  • Th1 - recognizes bacterialpeptide-MHC II complex → activates macrophage
  • Th2 - recognizes antigenicpeptide-MHC II complex → activates B cell

 

13

main subsets of CD4+ T cells

  • signature cytokines
  • immune reactions
  • defends host against...
  • role in disease

Th1 → IFN-gamma

  • macrophage activation; IgG production
  • intracellular microbes
  • autoimmune diseases, tissue damage associated with chronic infection

Th2 → IL4, IL5, IL13

  • mast cell, eosiniphil activation; IgE production; "alternative" macrophage activation
  • helminths
  • allergic disease

Th17 → IL17A, IL17F, IL22

  • neutrophilic, monocytic infl
  • extracellular bacteria; fungi
  • organ-specific autoimmunity

14

regulatory T cells 

(Tregs)

key for tolerance

recognition of self antigen in tissues or lymph nodes → Tregsexpress specific tf FOXP3

  • directly inhibit T cell activation and effector T cell fx
    • ​produce inhibitory molecules (CTLA-4)
    • affect DCs
    • express high levels of CD25 (receptor for IL2 - critical for T cells proliferation) → Tregs sequester IL2, prevent it from spurring Treg proliferation

15

why do we need such a large number of TCRs? 

(1015-1018)

peptides from pathogens are presented to T cells via MHC

  • need high variety/diversity of TCRs to recognize the variety/diversity of pathogens

issue: if pathogen mutates in a way that its peptides can't be presented to MHC → T cells can't respond!

  • ex. simian immunodeficiency virus (monkey analog of HIV) mutates rapidly to change the a.a.s that would anchor them to MHC (so as to avoid triggering immune resp!) → "CTL escape" hypothesis

 

16

issue: if pathogen mutates in a way that its peptides can't be presented to MHC → T cells can't respond!

 

how has the immune system evolved to deal with this?

100s of diff polymorphisms for each MHC gene

  • within a population, there will be individuals who can mount an immune response → population shouldn't be wiped out by one pathogen

TCRs are diverse, so as to be able to interact not just with pathogen peptide, but also MHC molecule 

  • caution: T cells need to be able to bind BUT not bind too avidly, lest they become activated too often → autoimmunity

17

so...need a ton of different T cells that are able to recognize/bind a high diversity of both pathogen peptides and MHC receptors BUT that won't bind too strongly

 

how do you get them?

T cell devp't

  • selects the useful TCRs
  • eliminates dangerous TCRs (extra-high MHC avidity)
  • ignores the rest

 

immature T cells (thymocytes) 

→ positive selection picks out useful T cells (based on TCRs)

  • throws out approx 95%! 

→ negative selection eliminates dangerous T cells

  • throws out approx 70% of the ones that pass positive selection!

**during positive and negative selection, T cells must be capable of selfpeptide-MHC complex recog/binding → how the immune system gets to know SELF before leaving they thymus and taking on the job of attacking NON-SELF 

 

stages of maturation:

[bone marrow] stem cell → [thymus] double negative T cell → double positive T cell → single positive immature T cell → [periphery] naive mature T cell

18

types of tolerance

1. central tolerance: thymus and bone marrow

  • removal of self reactive clones

2. peripheral tolerance

  • ignorance : hide "self" antigens
  • anergy : shut down self-reactive clones
  • suppression : use other molecules/proteins/cells to keep self-reactive clones in check

 

19

central tolerance : T cells

removal of self-reactive T cell clones in thymus

TCR-peptide-MHC affinity of thymocytes is positively/negatively selected

  • low affinity : death by neglect (apoptosis)
  • intermediate affinity : positive selection → survival, differentiation
  • high affinity (beyond threshold) → negative selection (apoptosis)
    • THIS IS THE CASE IN WHICH CENTRAL TOLERANCE COMES INTO PLAY

20

thymus characteristics

  • maturing T cells start in medulla, move to cortex and back over the course of their maturation
  • thymic fx decreases dramatically with age
  • TCR repertoire of naive and memory T cells changes with age
    • high diversity established in youth
    • small decrease in diversity, clonal size until approx 70
    • dramatic contraction in later life

21

bone marrow transplants

cure for leukemia and other cancers

  • hematopoeitic cells are killed by irradiation/chemo, but epithelial/stromal cells are not
  • when you replace with donor marrow, you end up with immune cells with donor genotype, epithelial/stromal cells with host genotype

patient age post-bone marrow transplant plays a role in susceptibility to secondary infection bc T cells do not reconstitute as well

22

key events in thymocyte development

 

1. multipotent stem cells (from HSC line) directed into T cell lineage

2. RAG 1/2 (recombinant activating genes) are expressed and mediate V(D)J recombo of TCR loci

3. positive selection : select based on affinity

4. negative selection : restrict based on affinity in excess of threshold

5. multiple lineages defined (CD4, CD8, Treg, etc)

23

MHC restriction of T cells

ex. T cells from one strain of mice that are selected to respond to a virus CANNOT respond to the same virus in a diff strain of mice

why? diff MHC!

  • selected TCR will only recognize the specific peptide it's selected for
  • TCR will only recognize the MHC it was "restricted" by