L24 - Immunological tolerance

Question 1

name the 3 different ways we produce such a diverse number of TCR and antibodies

Answer 1

1. V(D)J recombination:
   random comibination of different gene segments
2. Junctional diversity:
   random added nuceoltides between gene segements
3. pairing of different heavy and light chains (BCR/immunoglobulin) or alpha and beta chains (TCR)

Question 2

pro and con of antigen diversity

Answer 2

+:
diverse array of antigen receptors allow recognition to diverse array of pathogens

-:
receptors capable of recognising self/harmless antigens also randomly produced –> chance for autoimmunity

Question 3

what is the price we pay for diverse antigen receptor repertoire

Answer 3

self-reactive lymphocytes

= how do we prevent tyhese causing autoimmune disease ?

Question 4

define immunological tolerance

Answer 4

memchansisms to pprotect individual from self-reactive T and B cells –> prevent autoimmunity by ensuring slef-tolerance

= absence of immune response against self-antigens

Question 5

define Central vs Peripheral tolerance

Answer 5

Central:
immature lymphocytes in development in CENTRAL lymphoid organs

= Bone marrow –> B and Thymus –> T

Peripheral:
mechanisms directly act on mature lymphoytes in PERIPHERAL tissues

Question 6

name the gene that causes V(D)J recombination

Answer 6

RAG

= recombination activation gene

Question 7

dscribe positive and negative slectipn for t-cells in thymus

Answer 7

positive:
⍺βTCR that recognises self-antigen:MHC complex receives survival signal –> positively selected

negative:
TCR that recognises self-antigen:MHC with TOO HIGH AFFINITY undergoes apoptosis –> negatively slected

Question 8

what is death by neglect

Answer 8

TCR affinity too low in positoive slection

= do not receive any siurvival signals so die

Question 9

percetage of T cells that die in positive/negative selection

Answer 9

98%

Question 10

name 2 reasons self-reactive T cells survive selection in Central tolerance

Answer 10

1. not all self-antigens are expressed in thymus
2. weakly self-reactive t-cells may escape negative selection

Question 11

explain the AIRE gene in medullary thymic epithelial cells role in allowing self-reactive

Answer 11

thymus expresses a subset of self-antigens coded by AIRE

= not all antogens are presented
= self-reactive T cells may pass positive selection and bypass negative due to self-antigen not being present

Question 12

why might the limited number of self-antigens coded by AIRE not be a massive problem

Answer 12

some self-antigens are hidden from T-cells
- physically behind barrier

= if self-reactive TCRs that survive Central tolerance cannot find the specifc self-antigen = no autoimmune response

Question 13

name the 2 signals requied to activate T cells

Answer 13

1. TCR:peptide on APC
2. Co-stim signal - CD28-B7

Question 14

what are the co-stimulatary moclules to activate T cells

Answer 14

B7 on APC –> CD28 on T-cell

Question 15

what is anergy in T cells

Answer 15

only 1 of the 2 signals for T-cell activation

= TCR-peptide but NO CD28-B7

state of unresaponsiveness shwon by lack of proliferation and IL-2 secretion in response to antigen

= functional inactivation of self-reactive T cells

Question 16

describe Activation induced cell death (AICD)

Answer 16

deletion of self-reactive T cells in periphery

1. continous TCR activation on self-reactive T cell causes upregulation of Fas

= ‘death receptor’

2. binding of FasL to Fas causes apoptosis

Question 17

how does AICD differentaite between self-reactive peptide and foreign

Answer 17

Foreign antigens:
Trigger transient TCR activation = pathogen cleared → no prolonged FasL expression

Co-stimulation (CD28/B7) dominates, promoting survival/effector functions.

Self-antigens:
Cause chronic TCR stimulation = self-antigens persist

Repeated signaling shifts the balance toward Fas/FasL → apoptosis (AICD).

Question 18

what are immune priviged sites

Answer 18

specific tissues in the body where immune responses are highly restricted to prevent inflammation and damage to sensitive structures

sites limit lymphocyte entry + suppress immune activation, and EVEN tolerate foreign antigens (e.g., transplants) without rejection.

Question 19

what are the 4 features of immune priveleged sites that make them so unusual

Answer 19

1. Physical Barriers:
   Limited lymphatic drainage prevents presentation to immune cells.

Blood-tissue barriers restrict lymphocyte entry.

2. Local secretion of TGF-β + IL-10 to suppress inflammation.
3. Fas ligand (FasL) expression: Induces apoptosis in infiltrating immune cells.
4. Regulatory T Cells (Tregs):
   High presence of Foxp3+ Tregs to maintain tolerance

Question 20

what are Tregs

Answer 20

specialized subset of CD4+ T cells that suppress immune responses and maintain self-tolerance, preventing autoimmunity.

Question 21

how are Tregs produced

Answer 21

stronger affinity than normal ‘naive’ T-cells but not too strong to be negatively selected –> intermnediate affinity

Foxp3 transcription factor induced

Question 22

name the transcription factor Tregs rely on for function

Answer 22

Foxp3

Question 23

how do Foxp3 Tregs maintain peripheral tolerance

Answer 23

1. granezyme release:
   Granzyme B enters immune cells and induces apoptosis –> cleave ICAD and form apoptososme

= Directly eliminates activated self-reactive T cells

2. cytokine release:
   TGF-β: Inhibits T cell proliferation and promotes Foxp3+ Treg generation
3. downregulatiuon of B7:
   reduced co-stimulation causing anergy in T-cells
4. continously express Cd25:
   IL-2 high affinity receptor –> starves nearby T cells from IL-2

Question 24

what are the developmental stages of B-cells in bone marrow

Answer 24

pro-B cell –> pre-B cell –> immature B cell

= V(D)J recombination starts at pro

Question 25

what are the 4 fates for reactive B cells in bone marrow - B cells central tolerance

Answer 25

strong BCR affinity for self-antigen in bone marrow causes arresting of development 1. deletion 2. Receptor editing 3. Anergy 4. Ignorance

Question 26

what is receptor editing in B cells

Answer 26

rearrangment of genes encoding light chain immunoglobulin to replace self-reactive receptor = if new receptor is STILL self-reactive = apoptosis = if okay = normal development

Question 27

describe what anergy and immunological ignorance mean for self-reactive B cells in bone marrow

Answer 27

Anergy: permanent strate of unresponsiveness induced Ignorance: concentrations of self-antigen too low to stimulate B-cells --> antigen may be inaccesible or have very low affinity for BCR

Question 28

if self-reactive B cells encounter slef antigen in periphery they undergo peripheral tolerance mechanisms, like what ?

Answer 28

deletion by apoptosis anergy induced survival and maturation if no reaction --> not self-reactive

Question 29

describe B cell 'tolerance' due to a lack of T cell help

Answer 29

B cells require T cell help to produce high-affinity, class-switched antibodies = When self-reactive B cells fail to receive this help, they are silenced or eliminated, preventing autoantibody production 'tolerant' T cells continue to stimulate B cells despite them being self-antigens

Question 30

nakme 2 ways that T cells can NOT let self-antigen B-cells be tolerated

Answer 30

No CD40L signal: T cells either ignore the antigen or are deleted/anergized --> by Tregs No cytokines: Without IL-4/IL-21, the B cell cannot class-switch or form germinal centers.