54. T Cell Activation & Generation of Effectors Flashcards
The life stages of T lymphocytes
- Generated in bone marrow => undergo maturation in thymus
- Mature naïve T cells released from thymus into the blood
- Recirculate between blood and peripheral lymphoid organs (lymph nodes, spleen, MALT)
- If they encounter antigens that they recognise => lymphocyte activation, proliferation & differentiation into effector/memory cells
- Effector T cells => specialised functions
- Memory T cells => memory responses (faster, efficient)
T cell role in immune response
• Designed to fight intracellular microbes
- intracellular bacteria in phagosomes of phagocytes
- viruses: free in cytoplasm of cells (phagocytes or non-phagocytes e.g. epithelial cells)
- cancer cells (mutated proteins from cancer cells)
Antigen recognition by T cells
- T cells: do not recognise antigens directly
- T cells: recognise antigens only after processing and presentation
• Most T cells (αβ TCR T cells) recognise peptides
- T cells recognise cell-bound Ags (peptides)
- peptides from foreign Ags only when bound to major histocompatibility complex (MHC) molecules
• T cells recognise antigens via their T cell receptor (TCR)
=> similar structure to B cell antigen receptor (BCR)
=> 2 chains:
- α and β (most common TCR type)
- γ and δ (TCR in γδ T cells)
- each chain: 1 variable (V) domain + 1 constant (C) domain
- Antigen binding site formed by: Vα + Vβ
- V and C domains of TCR and BCR are homologous
Major histocompatibility complex (MHC)
MHC molecules display peptides from processed Ag
•MHC I: presentation of peptides to CD8+ T cells composed of α chain + β2-microglobulin
- all nucleated cells
- e.g. HLA-A, HLA-B, HLA-C
• MHC II: presentation of peptides to CD4+ T cells composed of α chain + β chain
- antigen presenting cells: dendritic cells macrophages
- e.g. HLA-DP, HLA-DQ, HLA-DR
Antigen presenting cells (APC)
Cells that specialise in the capture and presentation of antigens (Ag) to CD4+ T cells
Professional APCs:
•Dendritic cells => the only APCs capable to present to naïve T cells
•Macrophages => present to previously activated effector T cells
- CD8+ T cells recognise Ags displayed by nucleated cells (not just APC but also cells that are not APCs)
Dendritic cells
- skin, mucosa, tissues
capture microbes - transport microbes from tissues (e.g. epithelia) to draining lymph nodes
- process microbes =>Ags
- present Ags to naïve T cells
- activate naïve T cells
Signal 1: recognition of Ag (peptide:MHC complex) on APC
=> not sufficient to induce T cell activation
=> without signal 2 => no response or anergy of T cell
Signal 2: co-stimulation
=> binding of co-stimulatory molecules (B7 family, e.g. CD80/CD86) on APC by co-stimulatory receptor (CD28) on T cell
=> together with signal 1 => activation of naïve T cells
=> more important for naïve T cells than for restimulation of previously activated effector or memory T cells
=> APCs exposed to infection increase the expression of co-stimulatory molecules (B7) and of MHC
Infection increases the antigen presenting function of APCs
Signal 3: cytokines produced by APCs (after infection)
=> regulate the differentiation of activated T cells into different types of effector T cells
e. g. IL-12 and IFN-γ from APC => differentiation into Th1
e. g. IL-4 from APC => differentiation into Th2
=> ensure the right type of effector T cell is generated
e.g. effector T cell type that is most suited to respond to the infection that triggered the response
Th1 <=> macrophage co-operation
Th2 <=> B cell and eosinophils / mast cell co-operation
Functions of macrophages
=> phagocytose microbes (e.g. Mycobacteria tuberculosis)
=> Ag presentation to effector CD4+ T cells (Th1)
=> activation of Th1 cells
=> Th1 cells activate macrophage to kill ingested microbes
Antigen presentation to CD8+ T cells
All nucleated cells can present peptides derived from proteins from antigens present in the cytosol to CD8+ T cells
=> all nucleated cells can get infected by viruses
=> all nucleated cells can get cancer-causing mutations
=> CD8+ T cells (cytotoxic T cells, CTLs) specialised to:
- recognise viral antigens and mutated proteins
- eliminate cells infected by viruses/malignant cells
Antigen processing & presentation to CD4+ T cells
•Exogenous Ags (e.g. bacteria) taken up in cells, processed and presented by MHC II to CD4+ T cells
•Exogenous pathogens (bacteria that grow outside cells)
=> taken up by phagocytes
=> eliminated via killing in phagocytes
=> eliminated by antibodies (via neutralisation, opsonisation and complement activation)
CD4+ T cell effectors help macrophages (Th1) and B cells (Th2) to eliminate extracellular bacteria
Antigen processing & presentation to CD8+ T cells
Cytosolic Ags (e.g. viruses, mutated proteins in cancer cells) are processed and presented by MHC I to CD8+ T cells
Pathogens that grow free in the cytosol (viruses) or
Pathogens (bacteria, viruses) that are taken up in phagosomes but are then released into the cytosol
=> efficiently eliminated via killing by CD8+ T cells (CTLs)
CD8+ T cells specialised to eliminate cells infected by viruses and cancer cells
Types of effector T cells
•Th (helper) cells: express CD4 (CD4+ T cells)
- Th1: help phagocytes to kill ingested microbes
- Th2: help eosinophils/mast cells to kill helminths
- Th17: role in defense against bacteria & fungi
- Tfh (T follicular helper); help B cells (class switch and affinity maturation)
•Cytotoxic T lymphocytes (CTL):
- express CD8 (CD8+ T cells)
- kill cells infected by microbes that grow free in cytosol
•Regulatory T cells (CD4+CD25+FOXP3+):
- immune tolerance & inhibition of immune responses
Generation of Th1 effector cells & main roles
•Cytokines that induce differentiation into Th1
- IL-12 and IFN-γ
- from APC infected with bacteria (e.g. Mycobacteria, Listeria)
• Main cytokine produced by Th1: IFN-γ
• Main role Th1: activate phagocytes (macrophages)
=> inc. destruction of intracellular pathogens
• Other roles: stimulate production of IgG Abs
=> inc. phagocytosis of microbes
