Primary lymphoid organs
Thymus and bone marrow
Direction of maturation in thymus
Cortex -> medulla
Two classes of TCR
1) αβ T cell
2) γδ T cell
Double negative lymphocytes
- DN1-DN4
- In cortex
- No TCR, CD4 or CD8
- Determine αβ or γδ cell line
- Gene rearrangement of receptor chain
γδ T cell development
- Cells with γδ TCR arise first in embryonic development
- γδ leave thymus without any selection
- Migrate to mucosal and cutaneous tissues: first line defence
- Recognition of antigen not MHC-restricted!!
αβ T cell development
- Generation of double positive (DP) T-lymphocytes (CD4+ CD8+)
- Selected in thymus
- > Recognition of self MHC molecules (useless if not)
- > NOT recognition of self antigens (dangerous if it does)
Positive selection
Aim: recognize self MHC+peptide
- Test by cortical thymic epithelial cell
- Weak/no binding -> apoptosis
Negative selection (central tolerance)
Aim: differentiate self and foreign antigens.
Eliminate self-reactive T cells (bind tight to MHC+self peptide
- Test by dendritic cells
- Tight binding -> apoptosis
*Cannot eliminate T cells w/receptors specific for self peptides not expressed in thymus! These cells enter circulation.
Promiscous gene expression
1% of thymic medullary epithelial cells possess this
- Express many different genes
- T cells are selected for self antigens specific for different tissues - while in thymus!
AIRE
“Autoimmune regulator”: controls expression of self peptides by mTEC
Development of single positive T cell
Bind to MHC I (CD8+) or MHC II (CD4+) on thymic epithelial cell
Percentage of αβ T cells that survive selection to leave thymus as naive cells
Positive selection: 45 % survives
NEgative selection: 5 % survives
Where T cell and foreign antigen meet
Lymph node
How foreign antigen gets to lymph node
By immature dendritic cell via afferent lymphatics
T cell activation signals
Signal 1:
- Binding of peptide-MHC complex by TCR+co-receptor (CD4 or CD8)
Signal 2:
- Costimulation (APC: B7-CD28)
Activation of T cell by APC
1) MHC II-peptide binds TCR+CD4
2) Costimulation B7 binds CD28
3) Phosphorylation of CD3 ITAM motif
4) Signalling pathways->activate transcription factors
5) IL-2 mRNA transcribed
6) Autocrine activation by IL-2 -> T cell proliferation
IL-2 (T cell)
Autocrine growth T-cell-growth-factor
Immunological synapse leads to
- Lymphocyte activation
- Cytokine production
- Proliferation
- Differentiation
Negative costimulation APC-T cell
B7 binds to CTLA 4
Types of T-cells (by receptor)
- Conventional αβ T cells
- γδ T cell
- Non-conventional αβ NK T cell
Types of T-cells (by role)
- T effector cells (cytotoxic, helper, regulatory)
- Memory T cells
αβ T cells
- Naive CD8+
- Naive CD4+ (->Treg or Th)
T helper cell examples
- Th1: IFNγ, TNFα, IL-2
- Th2: IL-4, -5, -13
- Th9: IL-9, -10
- Th17: IL-17, -26, -22
- Th22: IL-22
- TFh: IL-21
Treg cytokines
TGFβ and IL-10
Cytotoxic T cell (CD8+)
- TCR+CD8
- Fas ligand (bind Fas of infected cell)
- Granules with: perforin and granzymes (released into infected cell)
CD4+ regulator cells
- Treg (TGFβ and IL-10)
- Tr1 (IL-10)
- Th3 (TGFβ)
CD4+ effector cells
- Th1 (IFNγ -> NK cells and macrophages)
- Th17 (IL-17 -> Inflammatory PMNs)
- Th2 (IL-4 -> Eosinophils, basophils, B-cells)
Th1 cells
- IFNγ, TNFα, IL-2
- Activates Tc cells, NK cells and macrophages
- Th1 and Th2 cells can inhibit eachother
Th2 cells
- IL-4, -5, -13
- Activated B-cells and eosinophils, basophils
If CD4+ cells have intermediate avidity in thymus
We get Treg cells
If CD4+ cells have moderate self/MHC avidity in thymus
We get effector Th cells
γδ T cells
- Interact with non-protein antigens that are not processed or associated with MHC molecules
- γδ TCR: pattern recognition -> activate γδ T cell -> can be either cytotoxic or helper
- Immunosuppressive
- Pleiotropic regulatory function
NKT cell
- Direct and indirect killing of virally infected and tumor cells
- Indirect: Secrete IFNγ -> activate NK or CD8+ T cell
- Direct: Has TRAIL and FasL on surface -> bind their receptors on tumor cell -> NKT cell release perforin and granzymes
- Has receptors for IL-12 and CD1d (on DCs)