T-Cell Activation & Generation of Effector Cells

Question 1

explain the types of adaptive immune responses?

Answer 1

B lymphocytes produces antibodies, involved in humoral immunity and targeting extracellular microbes

T lymphocytes are involved in cellular immunity and targeting intracellular microbes

Question 2

where are T and B cells generated?

Answer 2

bone marrow, T cells then migrate to the thymus where they mature

Question 3

name some peripheral lymphoid organs

Answer 3

lymph nodes, spleen, lymphoid tissue, mucosal tissues

Question 4

The life stages of T lymphocytes

Answer 4

generated in bone marrow, mature in thymus

mature naive T cells cells released from thymus into blood, recirculation between blood and peripheral lymphoid organs (lymph nodes, spleen, MALT)

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)

Question 5

MALT

Answer 5

mucosal associated lymphoid tissue

Question 6

T cells are designed to fight what?

Answer 6

intracellular microbes

1. intracellular bacteria in phagosomes of phagocytes
2. viruses: free in cytoplasm of cells (phagocytes or non-phagocytes e.g. epithelial cells)
3. cancer cells (mutated proteins from cancer cells)

Question 7

do T cells recognise antigens directly?

Answer 7

no, only after processing and presentation
T cells recognise antigens via their T cell receptor (TCR)

αβ TCR T cells recognise:

• cell bound peptides
• peptides from foreign Ags when bound to MHC

Question 8

TCR structure?

Answer 8

2 chains: alpha and beta are most common TCR type)

gamma delta is another type

each chain has 1 variable (V) domain + 1 constant (C) domain - antigen binding site consists of the V regions (V alpha and V beta)

Question 9

MHC I and MHC II presentation and structure

Answer 9

MHC I: presentation of peptides to CD8+ T cells
composed of alpha chain + beta 2-microglobulin

MHC II: presentation of peptides to CD4+ T cells
composed of alpha chain + beta chain

(γδ T cells recognise antigens that are not displayed by MHC I and MHC II)

Question 10

expression of MHC 1?

Answer 10

MHC I: all nucleated cells

Question 11

expression of MHC 2?

Answer 11

APC’s dendritIc cells, B cells

Question 12

what are APC’s?

Answer 12

cells that specialise in the capture and presentation of antigens (Ag) to CD4+ T cells

• CD8+ T cells recognise Ags displayed by nucleated cells (not just APC but also cells that are not APCs)

Question 13

professional APC’s

Answer 13

professional APC’s include

Dendritic cells

• skin mucosa tissues
• the only APCs capable to present to naïve T cells
• causes naive T cell activation, clonal expansion and differentiation into effector T cells
• transport microbes from tissues (e.g. epithelia) to draining lymph nodes

Macrophages

• present to previously activated effector T cells
• causes effector T cell activation and activation of macrophages
• phagocytose microbes
• activation of TH1 cells, which activate macrophage to kill ingested microbes

Question 14

DCs & signals for naïve T cell activation (slide 36)

Answer 14

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

• activation of naive T cells
• binding of co-stimulatory molecules (eg. CD86) on APC by co-stimulatory receptor (CD28) on T cell
• more important for naïve T cells than for restimulation of previously activated effector or memory T cells

Signal 3: cytokines produced by APCs (after infection)

• regulate the differentiation of activated T cells into different types of effector T cells
• eg. IL-4 from APC => differentiation into Th2
• ensure the right type of effector T cell is generated

(effector T cell type that is most suited to respond and help eliminate the infection that triggered the response)

Question 15

what does infection upregulate?

Answer 15

upregulates the co signaling molecules so there are more signal 2’s, and infection also makes it the dendritic cell a better APC

Question 16

Antigen processing & presentation to CD4+ T cells

Answer 16

Exogenous Ags (e.g. bacteria) taken up in endosome vesicles into the APC, broken down into antigenic peptides

MHC class II transported to the endosome, peptides are associated with the MHC class II - 1 peptide binds to the groove in the MHC molecule (called CLIP)

HLA-DM is involved in freeing the groove from the peptide. If MHC doesn’t find a peptide that fits in the groove it will be degraded in the late endolysosomal compartment.

If it does find a peptide from the bacteria, the peptide will bind to the MHC, it will be in the late endolysosomal compatment which will fuse with the plasma membrane to be expressed on the cell surface

Question 17

Antigen processing & presentation to CD8+ T cells

Answer 17

CD8+ T cells are less to do with bacteria

Recognise viral antigens/mutated proteins from viruses that grow free in the cytosol or bacteria/viruses taken up in phagosomes and released into the cytosol

CD8 cells eliminate cells infected by viruses, and cancer cells

Cytosolic Ags processed and presented by MHC I to CD8+ T cells

Degradation of proteins and transport of peptides from cytosol to lumen ER by TAP

MHC I is also there with a free groove, looks for a peptide that fits, and if it finds one, it leaves via the golgi in a vesicle, fuses with the plasma membrane and presents on the surface of the cell and CD8 recognises it via the TCR.

Question 18

Types of effector T cells

Answer 18

1. 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)
2. Cytotoxic T lymphocytes (CTL):
   express CD8 (CD8+ T cells)
   kill cells infected by microbes that grow free in cytosol
3. Regulatory T cells (CD4+CD25+FOXP3+):
   immune tolerance & inhibition of immune responses

Question 19

Generation of Th1 effector cells & main roles

Answer 19

Cytokines (IL-12, IFN-gamma) that induce differentiation into Th1, produced by APC’s infected with bacteria (e.g. Mycobacteria, Listeria)

Main cytokine produced by Th1: IFN gamma

roles: 
activate phagocytes (macrophages), increasing destruction of intracellular pathogens

stimulate production of IgG Abs
acts as opsonins, increasing phagocytosis

Question 20

Generation of Th2 effector cells & main roles

Answer 20

IL-4, IL-25, IL-33, from APC’s/cells infected by helminths

Main cytokines produced by Th2: IL-4, IL-5, IL-13

roles:
help B cells produce IgE, which opsonise helminths
activates eosinophils & mast cells
eosinophil & mast degranulation and killing of helminths

IgE – antibody good for targeting parasites like helminths
-mast cells have the right granules to cut through the thick skin of parasites

Question 21

Generation of CTL CD8+ T effector cells

Answer 21

Ag recognition by naïve CD8+ T cells in PLOs
activation, proliferation, differentiation into effectors

Effector CD8+ T cells leave activation site (PLO) via blood, perform their effector functions to eliminate Ag/infection

Question 22

main role of CD8+ cells

Answer 22

• recognise viral antigens and mutated proteins
• eliminate cells infected by viruses/malignant cells

kill infected cells, antigen-specific and contact-dependent

Killing mediated by cytolytic molecules:

1. Perforin: forms pores => delivery of granzymes
2. Granzymes A, B, C: initiate apoptosis

delivered at the site of contact between CTL and target, prevents killing of neighbouring healthy cells

killing mediated by death receptor pathway (Fas/FasL)