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Flashcards in T cells Deck (23):
1

Stages of T cell Development?

Common lymphoid progenitor
--> IL-17
--> T cell linage

--> Migration to Thymus
--> VDJ/TCR rearrangement
--> Negative selection
--> AIRE
--> Positive selection

2

T cell selection process?

Negative selection:
- TCR with high affinity for self are deleted OR become regulatory T cells

Positive selection:
- T cells with TCR capable of interacting with self-MHC survive

3

Role of AIRE in T cell development?

Autoimmune regulator

AIRE controls expression of tissue specific antigens in the thymus

T cells who react with high affinity to self antigen are deleted

4

What is the disease associated with dysfunctional AIRE?

Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy - APECED

Autosomal recessive disorder --> mutated AIRE gene
--> failure to express tissue specific antigens
--> Failure to delete autoreactive T cells
--> Autoimmunity

Results in:
Chronic mucocutaneous candidiasis
Autoimmune hypoparathyroidism
Autoimmune Addisons disease

5

Role of peripheral T-cell tolerance?

Chronic and recurrent presentation of self antigens in the periphery without co-stimulatory signals --> apoptosis

* CD80/86 only expressed in response to Ags which engage innate PRRs *

Clonal ignorance in immunological privileged sites

Suppression by T-reg cells

6

Role of T-reg cells?

Express foxP3
--> reinforces regulatory phenotype - CTLA-4 and IL-10
--> blocks transcription of IL-2 gene

Results in reduction in immune response
Suppress auto-immunity and atopy

7

Subsets of T-reg cells

Thymic T-reg cells:
- Apoptosis of autoreactive T cells
- Formation of new T reg cells

Peripheral T-reg cells
- form in response to food antigens, commensal bacteria and allergens

8

Mechanisms for suppression by T-reg cells?

CTLA-4
- Down-regulate CD80/86

Secrete inhibitory cytokines - IL-10, TGF-beta, IL-9
Restrict IL-2 access by T cells - CD25
Cytolysis

9

Disease associated with loss of FoxP3?

Immune dysfunction, polyendocrinopathy, enteropathy,

AR X-linked disorder
Frequently fatal

DM, Thyroiditis
Enteropathy
AIHA
ITP
Atopy - eczema, food allergies, eosinophillia

10

What is required to activate T-cells?

MHC + peptide + costimulation signals

CD80/86 on T cells bind:
- CD28 = activation
- CTLA-4 = deactivation
- PD-1 = inhibitory

11

CTLA-4 therapies?

Abatacept:
- CTLA-4 Ig
- Blocks T cell activation

Ipilumumab:
- CTLA-4 Ab
- Stimulates immune response

12

Stimulation of B-cells

CD-40 from T-cell bind CD-40 ligand on B cell

--> activation and proliferation

13

Hyper-IgM syndrome

Absent CD-40-CD40L signal
--> failure of B cell isotype switching and memory B cell generation

Results in:
- Recurrent bacterial infections - PCP
- Diarrhoea
- Cancer
- Autoimmune diseases

High IgM and Low IgG, IgE, IgA
Normal B cells

Treat with IVIG, bactrim, G-CSF

14

Role of Th-1 cells?

Differentiate in response to IL-12 and IFN-alpha

Secrete IFN-alpha, TNF anf lymphotoxin

Activates macrophages
Activates NK cells
Acts on B cells to isotype switch and form antibodies

15

Th-1 cells and mycobacterial immunity

Mendelian susceptibility to mycobacterial disease

Genetic deficiency of Th1 pathway components

--> susceptible to:
- Non TB mycobacteria
- TB
- BCG vaccine
- Invasive salmonellosis

16

Role of Th-2 Cells?

Differentiate in response to IL-4

Secrete IL-4, IL-5, IL-6, IL-10, IL-13

B cell isotype switching to IgE
Activate eosinophils

Atopic response and helminth defense

17

Role of Th-17 Cells?

Differentiate in response to IL-1, IL-6 and IL-23

Secrete IL-17 and IL-22

Stimulates the release of chemokines and cytokines to attract neutrophils
Defensin secretion --> increased barrier function

Defense against candida and staph

18

Role of IL-17 in psoriasis?

IL-17 has a critical role in psoriasis pathogenesis
Stimulates keratinocytes

Anti IL-17 treatments - Secukinumab and brodalimumab

Anti IL-22 treatments - ustekinumab

19

Disease caused by IL-17 deficiency?

Chronic mucocutaneous candidiasis

Th-17 deficiency

--> chronic, recurrent candida infections

20

Diseases caused by lack of T cells?

Infection with intracellular organisms

Fungi
CMV
EBV
VZV
HSV
PCP
Listeria
MAC
TB

21

What is SCID?

Severe combined immune deficiency

FTT and recurrent opportunistic infections
Risk of autoimmunity and malignancy

Genetics:
- IL-7 receptor deficiency
- RAG1 or 2 deficiency
- Gamma common chain deficiency

22

What is idiopathic CD-4 T cell Lymphopenia?

Low CD-4 count without evidence of HIV

Recurrent opportunistic infections
CD-4 count <300

Treat with prophylaxis for infections

23

Role of follicular helper cells and ICOS?

Help B cells
• class switching
• affinity maturation