Lecture 3 - Antigens and Cytokines (Part 2)

IL-1α & IL-1β

• Inflammatory

• Made by DCs, monocytes/macrophages

IL-1α

intracellular; released w/cell damage, death

IL-1β

systemic effects

• Phagocyte activation

• Fever, inflammation

• Acute-phase protein production

IL-1RA

inhibitor; anti-inflammatory

• Also made by DCs, monocytes/macrophages

• Blocks the IL-1 receptor

IL-1α, IL-1β, IL-1 receptor…

antagonist (IL-1RA)

Tumor necrosis factor-α (TNF-α)

• Made by lymphocytes, monocytes/macrophages, others

  • Made by activated macrophages- amplifies response

Tumor necrosis factor-α (TNF-α) function 

• Several functions- inflammation, T cell activity

• Acute-phase response, fever

  • ↑ vasodilation, vascular permeability

  • ↑ adhesion molecule & chemokine expression on vessels

  • ↑ antigen presentation

• Highly inflammatory; response to Gram-negative bacteria

  • LPS: septic shock, in high amounts

• Role in several autoimmune diseases

Interleukin-6

• Made by many cell types; different functions

• Monocytes/macrophages, T & B, endothelial cells

Interleukin-6 function

• Depending on biological context/other cytokines

• Part of cascade contributing to inflammation

  • Induced by IL-1

• Induces acute-phase proteins

• Stimulates T & B cells

  • Pro-, anti-inflammatory cytokines from CD4+ T cells

  • B cell proliferation, antibody production

Transforming growth factor (TGF)-β

• Produced by several cell types

• Inhibitory, anti-inflammatory, regulatory

• ↓ some T cell responses

• ↓ macrophage activation

Interferon (IFN)-α and -β

• “Type I interferons”

• Made by subtype of DCs

• Disrupt viral replication

  • Activate natural killer (NK) cells

  • ↑ presentation of viral antigen by infected cells

Chemotaxis

induce movement, migration of cells

Chemokines

• Induced by various cytokines

• E.g., IL-6 and TNF-α

• Part of inflammatory response

• Different structural families: cysteines at N-terminus

  • CXC, CC, C, CX3C

CXC, CC, C, CX3C - What does X equal?

X = an amino acid

Chemokines - Responsible for directed movement of WBCs

• Receptors for a single chemokine on multiple WBC types

• Receptors for multiple chemokines on a single WBC

• Movement along concentration gradient to where needed

CXCL8 =

IL-8

Adaptive Response Cytokines

• Often made by innate cells

  • To promote specific lymphocyte response

• Often made by helper T (Th) cells

• To exert effect of Th cell type

• Broadly categorized by Th cell subset

  • Th1, Th2, Th17, Treg cells

Th1 and Th2 / Th17 and Treg cells

Reciprocal development 

Adaptive Response Cytokines

1. Th cells recognize Ag presented by APCs

2. Cytokines direct development into subset

3. May be made by APC or by other nearby cells

4. IL-12 → Th1: Cell-mediated immunity

5. IL-4 → Th2: Humoral (Ab) response

6. TGF-β + IL-6 → Th17: Extracellular microbes/fungi and Mucosal defense

7. TGF-β → Treg: Regulation/inhibition

IL-12 → Th1

Cell-mediated immunity

IL-4 → Th2

Humoral (Antibody) response

TGF-β + IL-6 → Th17

Extracellular microbes/fungi and Mucosal defense

TGF-β → Treg

Regulation/inhibition

Th1 Cytokines

Interleukin-12, IFN-γ (prototypical Th1 cytokine), and IL-2

Interleukin-12

• DCs, macrophages, others

• Induces Th1 lineage

• Enhances NK cell activity

IFN-γ: prototypical Th1 cytokine

• ↑ MHC expression (Ag presentation)

• Activates macrophages

• More robust activity

• Killing of intracellular microbes

• Regulates NK, cytotoxic T cells

• Induces more Th1 differentiation

IL-2

• Proliferation of T & B cells

• Enhances NK cell activity

Th2 Cytokines

IL-4 and IL-10

IL-4

• Basophils, Th2 cells

• ↑ IL-5, IL-13

• Parasite response; allergy

• ↑ Ag presentation, APC activity

• Stimulates eosinophils

• Production of certain Ab subclasses

IL-10

• Anti-inflammatory

• Monocytes/macrophages, Th2 cells, Treg cells, others

• ↓ Ag presentation

• ↓ IL-12 production, Th1 response

Th17 Cytokines

IL-17 and IL-23

IL-17

Inflammatory

• Recruits neutrophils

• Induces TNF-α, IL-6, IL-1β, IL-8

• Many non-immune cells

• Connective tissue-related

IL-23

• Differentiating/survival factor for Th17 cells

• Made by DCs, macrophages

• Dysregulation: several autoimmune diseases

Treg Cytokines

• CD4+CD25+Foxp3+ T cells

  • Develop in thymus (natural Treg)

  • Develop in periphery (induced Treg)

• Induced by TGF-β, anti-inflammatory environment

• Produce IL-10, IL-35

  • Inhibitory, anti-inflammatory

Hematopoietic Growth Factors

• Direct effects on enhancing cell responses

• Amplifies immune response to specific pathogens

• Proliferation/differentiation of progenitors in bone marrow

  • Colony stimulating factors (CSFs)

  • IL-7: required for lymphoid lineage

• IL-3: may work with various CSFs

  • Formation of platelets, RBCs, various WBCs

IL-7

required for lymphoid lineage

IL-3

Formation of platelets, RBCs, various WBCs

• may work with Colony stimulating factors 

Granulocyte-macrophage colony-stimulating factor (GM-CSF)

Non-lymphocyte WBC direction (towards myeloid branch)

Macrophage colony stimulating factor (M-CSF)

Monocyte/macrophage lineage

Granulocyte colony stimulating factor (G-CSF)

Neutrophil lineage

IL-3 + GM-CSF

• Basophils and mast cells

• Eosinophils

Erythropoietin

RBC production

• Prescribed for anemia; increase O2