8 - T-cell immunity

intracellular pathogens

viruses (CD8)

intracellular bacteria (CD4)

extracellular pathogens

extracellular bacteria

parasites

fungi

naive T cells

mature T cells that haven’t encountered their Ags

effector T cells

differentiated T cells that have acquired anti-pathogen activities

• after encountering their specific Ags presented by MHC molecules on APCs

memory T cells

long-lived Ag experienced

• enhanced Ag response

• provides protection from same pathogens

where are T cells found in lymphoid organs

T cell zone closer to BVs

where are B cells found in lymphoid organs

B cell follicles further from BVs

T cell chemokines

express: CCR7

respond to: CCL19 and CCL21

B cell chemokines

express: CXCR5

respond to: CXC13

lymphocyte entry into lymphoid tissues steps

1. rolling

2. activation - chemokines CCL21

3. adhesion- LFA-1

4. diapedesis - chemokines CCL21, CXL12

lymphocyte entry into lymphoid tissues rolling

• mediated by selectins (L-selectin)

L-selectin

mediates interaction w/ carbohydrate moieties of addressins

• in HEV and mucosal endothelium

lymphocyte entry into lymphoid tissues activation

mediated by chemokines (CCL21)

lymphocyte entry into lymphoid tissues adhesion

naive T cells to HEV

• mediated by integrins (LFA-1)

lymphocyte entry into lymphoid tissues diapedesis

transmigration of naïve T cells across endothelial cell wall toward chemokines in T cell zones in peripheral tissues

• mediated by chemokines (CCL21, CXL12)

HEV addressins

CD34 and GlyCAM-1

mucosal endothelium addressin

MAdCAM-1

integrin for all T cells

LFA-1

• alpha L + beta 2

what does LFA-1 interact w/

ICAM1 on HEV + APCs

• adhesion to endothelial or APCs

integrin for naive T cells

LPAM-1

• alpha 4 and beta 7

what does LPAM-1 interact w/

MAdCAM-1 on mucosal endothelial cells

• directed to migrate mucosal lymphoid tissues

integrin for activated effector T cells

VLA-4

• alpha 4 and beta 1

what does VLA-4 interact w/

VCAM-1 = expressed on activated/ inflammed endothelial cells

• migrate to infected/inflammed tissues

integrin deficiency

leads to leukocyte adhesion deficiency syndrome

ICAM-1 ligands

LFA-1, Mac-1

ICAM-2 ligand

LFA-1

VCAM-1 ligand

VLA-4

integrin deficiency

leads to leukocyte adhesion deficiency syndrome

integrin activation by chemokines

1. L-selectin

2. CCL21-CCR7 activates LFA-1

3. tighter interaction with ICAM-1

4. T cells cross endothelium

naive T cell recognizes Ag on mature DC

• downregulates S1P receptor

• proliferates

• differentiates → effector + memory

naive T cell DOES NOT recognizes Ag on mature DC

migrates out via efferent lymphatics

S1P

Sphingosine-1-phosphate, a blood borne lipid mediator

• attracts T cells + they will leave peripheral through efferent

fingolimod (FTY720)

antagonist of S1P

• blocks T cell trafficking

• treatment for multiple sclerosis

how are naive T cell primed

APCs in peripheral lymphoid tissues

professional APCs

DCs, macrophages and B cells

macrophages

scavengers that can be induced by pathogens to present Ags to naive T cells

T cell responses are initiated in ______ by __________

secondary lymphoid organs, activated DCs

distribution of DCs

T cell zone

distribution of macrophages

everywhere in lymph nodes

• more concentrated at marginal sinus + medullary cords

• mainly present Ags from intracellular pathogens

distribution of B cells

present Ags from various pathogens

conventional DCs

• derive from myeloid progenitors

• efficient in presenting Ags and priming T cells

• express MHC1 and 2

plasmacytoid DCs

• derive from lymphoid progenitors

• powerful in producing type 1 IFNs

• help cDCs present Ag

• express TLR-7 and TLR-9

immature DCs in peripheral tissues

• many long processes + endocytic vesicles containing MHC + lysosomal proteins

• cannot stimulate naive T cells

• recognize + ingest Ags

activated DCs

leave tissues and migrate through the lymphatics to secondary lymphoid organs -- MATURE

mature DCs in lymphoid tissues

• do not phagocytose

• high levels of peptide:MHC on the surface -

• express co-stimulatory ligands/receptors

• up-regulates adhesion molecule

• good at priming naïve CD4 and CD8 T cells

MHC-2 Ag presentation

presents Ag of endocytic system

• through receptor-mediated phagocytosis + macropinocytosis

• prime + activate CD8

MHC-1

presents Ag in cytosol

• cross-presentation

• transfer from incoming DC → resident DC

cross-presentation

Ag taken up by the endocytic pathways may be further delivered into in the cytosol, allowing presentation by MHC class I

infected skin wound

• effector T cells

leave lymph node + migrate to skin would

infected skin wound

• Langerhans cells

immature DCs of skin epithelium

• locally take up Ags

• differentiate + migrate to nearing lymph node

• cannot prime naive T cells

infected skin wound

• mature Langerhans cells

can transfer Ags to resident DCs

• presentation of MHC-1 Ags to naive CD8 T cells

• days later CD4 and CD8 will migrate to injured skin

immature DCs express innate immune receptors that recognize _______, which trigger phagocytosis

PAMPs

• TLRs

• C-type lectin receptors: dectin-1, DEC205 or DC-SIGN

• chemokine receptors CCR1,2,5,6

PAMP-induced innate immune receptor

Signaling in immature DCs triggers their activation to become “licensed”, and to migrate to lymphoid organs

activated DCs mainly express

CCR7, MHC 1+2, co-stimulatory molecules and adhesion molecules

B cells usually present Ags to______________

primed CD4 effector T cells NOT naive

• surface IgM binds to Ags

• Ags internalized to receptor-mediated endocytosis

  • Ags processed + presented w/ MHC2

DC Ag uptake

macropinocytosis + phagocytosis by tissue DCs

macrophage Ag uptake

macropinocytosis + phagocytosis

B cells Ag uptake

Ag-specific receptor

DC Ag effect

activates naive T cells

macrophages Ag effect

results in activation of macrophages

B cells Ag effect

results in delivery of help to B cell