Cytokines and Chemokines Lecture Notes

Cytokines

• Soluble factors produced by innate and adaptive immune cells.
• Mediate communication between immune cells and cells outside the immune system.

Importance of Cytokines

• Lymph Node: Organized structure maximizes interactions between antigen-specific T cells and antigen-presenting cells.
• Lung: Alveolar macrophages communicate via soluble factors (cytokines).
• Cell Contact Dependent Mechanisms: Cytokines amplify or stabilize cell-cell interactions (e.g., immunological synapse).
• Cytokines produced by T cells act on dendritic cells, and vice versa.
• All immune cells can produce and respond to multiple cytokines, forming a network for immune response coordination.

Cytokine Characteristics

• Low molecular weight proteins.
• Produced by cells to act on nearby or distant cells by binding to cell surface receptors.
• Provide positive and negative signals, enhancing or suppressing immune responses.
• Typically not stored in cells (exception: mast cells).
• Synthesis starts after stimulation (TCR, BCR, innate signaling).
• mRNA is short-lived, ensuring transient expression.

Types of Cytokines

• Interleukins (IL-1 to IL-37).
• Interferons.
• TNF (Tumor Necrosis Factor) and TNF superfamily (TNFSF).

Classifications Based On:

• Biological activities (e.g., interferons interfere with viral replication).

• Pro- or anti-inflammatory functions:

  • Pro-inflammatory: IL-1, IL-6, TNF.
  • Anti-inflammatory: IL-10, TGF-$\beta$.

• T helper cell cytokines (e.g., IFN-$\gamma$, IL-4).

• Receptor structure.

• Cellular sources:

  • Lymphokine (produced by lymphocytes).
  • Monokine (produced by monocytes, macrophages).

• IL-12: Produced by dendritic cells and macrophages (innate cytokines, monokines).

• IFN-$\gamma$: Produced by NK cells and CD4 T cells (lymphokines).

Cytokine Receptors

• Consist of multiple subunits (receptor subunits or chains).
• Extracellular domain: For cytokine binding.
• Cytoplasmic tail: For signal transduction initiation.
• Five types:
  • Type I.
  • Type II.
  • TNF.
  • IL-1.
  • G protein-coupled receptor (used by chemokines).
• Most interleukins bind to type I cytokine receptors (e.g., IL-2, IL-3, IL-4).
• IL-10 and IL-20 bind to type II cytokine receptors.
• Type II receptors are largely utilized by interferon cytokine families.

Regulation of Cytokine Action

• Regulation of cytokine receptor expression.
• Short lifespan of secreted cytokines.
• Short-distance action (50-150 microns).

Common Cytokine Properties

• Pleiotropic: IL-12 acts on both CD4 and NK cells.
• Redundant: IL-12 is essential for Th1 response, while IL-18 is not always necessary.
• Synergistic: IFN-$\gamma$ and TNF both activate macrophages.
• Antagonistic: IL-10 suppresses macrophage activation.

Cytokine Functions

• Regulate immune responses.
• Growth factors for immune and non-immune cells.

Common Pro-inflammatory Cytokines

• IL-12.
• TNF.
• IL-1.
• IL-6.
• Type I interferons.

Cytokines from Adaptive Immunity

• Interferon gamma (from Th1 cells).
• IL-4 (from Th2 cells).

Interferon Family

• Discovered for interfering with viral infection.
• Regulate cell proliferation and survival.
• Regulate immune system and cancer.
• Three types:
  • Type I.
  • Type II.
  • Type III.

Type I and Type III:

• Detected during viral infection.
• Produced by tissue cells and innate immune cells.
• Critical for antiviral immunity.

Type II (Interferon Gamma):

• Produced by activated lymphocytes (NK cells, CD8 T cells, CD4 T cells).
• Controls intracellular bacteria and parasites.

Type I Interferons

• Large family (e.g., IFN-$\beta$, 13 IFN-$\alpha$ subtypes).
• Mediate early innate immune response to viral infection.
• Blockade leads to uncontrolled viral infection.
• Viral nucleic acids are potent stimuli.
• Antiviral action mediated through paracrine signaling (acting on neighboring cells).
• Induce antiviral molecules that inhibit viral protein synthesis and degrade viral RNAs/DNAs.

Type II Interferon (Interferon Gamma)

• Produced by NK cells and activated T cells.
• Activates macrophages.
• Upregulates MHC class I and class II molecules.
• Induces antimicrobial substances (e.g., nitric oxide).

Cytokine Action in Context

• Autocrine: Cytokine acts on the same cell that produces it.
• Paracrine: Cytokine acts on neighboring cells.
• Endocrine: Cytokine enters bloodstream and acts on distant organs.

TNF (Tumor Necrosis Factor)

• Major mediator of acute inflammation (bacterial, viral infections).
• Produced in response to bacterial infection (gram positive and negative).
• LPS is a potent stimulus for TNF production.
• Produced by innate (macrophages, dendritic cells, neutrophils) and adaptive immune cells (Th1 cells).
• Pre-stored in mast cells.
• Interferon gamma enhances TNF production by innate cells.

Local vs. Systemic Activation:

• Low levels of TNF stimulate recruitment of neutrophils and monocytes.
• TNF induces endothelial cells to upregulate adhesion molecules.
• Stimulates production of other inflammatory cytokines (IL-1, IL-6).
• Induces dendritic cell migration to lymph node.
• Massive TNF production can lead to systemic effects:
  • Fever (acting on hypothalamus).
  • Production of acute phase proteins by hepatocytes.
  • Muscle and fat wasting (cachexia) in chronic inflammation.
  • Pathogenic effects: slows heartbeat, induces intravascular thrombosis, organ failure, affects glucose metabolism.

Cytokines in Homeostasis

• Function as survival and growth factors for blood cells.
• Needed for development and differentiation of blood cell lineages.

Chemokines

• Subset of cytokines involved in cell movement (chemotactic cytokines).
• Subdivided into families based on cysteine residues.
• Produced by microbial products and cytokines.
• LPS triggers chemokine production by macrophages.
• IL-17 enhances neutrophil response.
• Chemokine receptors expressed on all leukocytes.
• Receptor-ligand system is highly redundant (one receptor binds multiple chemokines).
• Hypothesis: Redundancy as a safety mechanism.

Functions:

• Modulate cytoskeleton structure and regulate cell motility.
• Development of lymphoid organs.
• Required for dendritic cell migration to lymph nodes for T cell priming.
• Activate leukocytes to enter sites of infection or injury.
• CCR5 and CCR4 are co-receptors for HIV.
• Chemokines act on integrins (heterodimer cell surface proteins).
• Integrins exist in low-affinity state during rest.
• Chemokine activation leads to conformational change, increasing affinity and interaction with adhesion molecules.
• Specialized stromal cells produce chemokine (CCR21), interacts on CCR7 expressed on the naive T cells and anchors all the naive T cells in this specialized region.