T cells vs B cells

• T cells and B cells are both lymphocytes produced in the bone marrow.
• T cells migrate to the thymus for differentiation into Helper T cells, Regulatory T cells, and Killer T cells.
• B cells stay in the bone marrow and migrate to secondary lymphoid tissues for differentiation into Plasma cells upon infection.
• Lymphocytes are mobile cells that circulate in the blood and lymph, visiting secondary lymphoid organs like lymph nodes to scan for foreign antigens.
• Lymphocytes bind to receptors on High Endothelial Venules (HEVs) to exit circulation and enter lymph nodes via afferent lymphatics.
• T cells are directed to the paracortex, while B cells are directed to the follicles within lymph nodes.
• Naïve T cells in the lymph node paracortex use TCRs to recognize antigen fragments presented on interdigitating dendritic cells.
• T cells that recognize an antigen become activated and stay in the lymph node; otherwise, they exit via efferent lymphatics and re-enter the blood.

Third Law of Immunity

• The immune system regulates itself to prevent excessive or self-destructive activity.
• CD8 T cells interact with MHC Class I, presenting peptides from intracellular infections.
• CD4 T cells interact with MHC Class II, presenting peptides from extracellular infections.

T Cell Activation Signals

• T cells require multiple signals to become activated.

TCR Recognition (Signal 1)

• TCR binding to MHC causes phosphorylation of the CD3 protein complex.
• Phosphorylation activates calcineurin, increasing intracellular Ca2+ and activating T-cell receptors.
• Ciclosporin (Atopica) inhibits calcineurin action, thus inhibiting T cell activation.

Danger Signals (Signal 2)

• Dendritic cells release danger signals after contacting pathogens, becoming APCs.

• T cells from an infected area have CD28 receptors.

• Danger signals induce CD80/CD86 molecules on the pathogen, which bind to the CD28 receptor, creating a signal alongside the TCR signal for co-stimulation.

• If the antigen is harmless, no binding to the CD28 receptor occurs, leading to T cell anergy.

• Signal 3 involves the innate immune system using PAMPs and PRRs.

• Naïve T cells undergo clonal expansion upon initial activation.

• Interleukin 2 (IL-2) acts as a T cell growth factor (autocrine signaling) to proliferate the T cell clone.

• T cells differentiate into mature effector forms under IL-2.

• CD8 T cells differentiate into killer T cells (cytotoxic T lymphocytes or CTL).

• CD4 T cells can differentiate into helper T cells or regulatory T cells.

• After the immune response, T cells become memory lymphocytes, providing long-term immunological memory as they patrol in the circulation.

Cytokines

• T cells produce cytokines as a key effector function.
• Cytokines are small proteins that aid cell signaling, acting as immunological hormones.
• They primarily act via a local paracrine effect, but sometimes via an endocrine effect.

Examples of Cytokines

• Interleukins:
  • IL-2: clonal proliferation of T cells.
  • IL-4: B cell growth factor.
  • IL-10: immunosuppression.
• Interferons:
  • IFN alpha/IFN beta: anti-viral defense (innate immunity).
  • IFN-gamma: macrophage activating factor.
• Tumor Necrosis Factor (TNF) Family:
  • TNF-alpha: cell killing.

Cytokine Receptor Signalling

• JAK/STAT pathway:
  • Cytokines released from immune cells bind to receptors on the cell surface, activating JAK proteins.
  • JAK proteins activate STAT proteins.
  • STATs enter the nucleus to switch genes on.
  • Oclacitinib (Apoquel) selectively inhibits JAKs, blocking the cytokine signaling pathway and blocking IL-31 receptors on nerve cells.
  • Ilunocitinib (Zenrelia) is less selective but also inhibits JAKs.

CD8 Killer T Lymphocytes

• Killer T cells differentiate from CD8 T cells in secondary lymphoid tissues.
• These T cells leave secondary lymphoid tissues and enter the circulation to find infected tissues.
• Killer T cells have altered homing receptors to target inflamed endothelium.
• Upon contact with an infected cell, they kill the cell via three pathways:

Cytokines Release

• JAK/STAT pathway is activated.
• Macrophages are activated and B-cells are assisted.

Cytotoxic Granules

• Contain perforin that forms pores in the cell membrane, allowing granzymes to enter the target cell.
• Granzymes activate the caspase cascade, causing cell death and stopping viral replication.

FAS Ligands

• Cytotoxic cells have FAS ligands, which bind to FAS receptors on normal cells.
• This activates a self-destruction sequence.

Innate Immune System Impact

• Pathogen-Associated Molecular Patterns (PAMPs) are molecular structures found in pathogens but not host cells that can be detected as foreign.
• Pattern-recognition receptors (PRRs) detect PAMPs.
• Dendritic cells have PRRs that induce the expression of CD80/CD86.
• Different PRRs induce different cytokine patterns, influencing CD4 T cell differentiation (signal 3).
• Bacteria acts on PRR 1, which causes the release of IL-12 to T cells, which then become CD4 T helper type 1 cells.
• Parasites act on PRR 2, which causes the release of IL-4 to T cells, which then become CD4 T helper type 2 cells.

CD4 T Cell Sub-Populations

• CD4 T cells can differentiate into several types with different roles.
• Most important are T Helper 1's and T Regulatory 1's.
• Dendritic cells release a danger signal (signal 2) to help differentiate the T cells into helper T cells.

T Helper Cells

• There are 2 main types of CD4 T-helper cells:

TH1 Helper T Cells

• Macrophages interact with TH1 cells.
• They release IFN-gamma, a macrophage activation factor, which helps:
  • The respiratory burst: increased Oxygen free-radicals, Nitric Oxide production, anti-microbial peptides and proteases. This enhances cellular aerobic metabolism for oxidative killing.
  • Increased lysosomal digestion.
• Important in vesicular infections where pathogens deliberately infect macrophages (e.g. mycobacteria such as TB).

TH2 Helper T Cells

• B-cells interact with TH2 cells.

• These activate B cells to make antibodies that are specific to the type of infection (e.g., IgG vs IgA vs IgE).

• Without the help of TH2's, only IgM are produced for a short period of time.

• The balance between TH1's and TH2's is important.

• In most infections, an equal amount of both TH1's and TH2's is needed.

• In vesicular infections of macrophages (e.g., mycobacterium bovis), TH1's are more important, TH2's are useless.

• In parasitic infections, TH2's are more important than TH1's.

• E.g., in parasitic infections, IgE antibodies are needed instead of IgM antibodies, TH1's are useless.

TH17 Cells

• These cells release IL-17
• They are used in mucosal epithelial immunity.
• When mucosal surfaces have been infected by bacteria or fungi, IL-17 activates epithelial cells to secrete anti-microbial peptides into the lumen and chemokines basally that draw the neutrophils to the area for phagocytosis of bacteria and fungi.

Regulatory T Cells

• These are the 'military police' of the immune system.
• They produce immunosuppressive cytokines like IL-10 and TGF-beta.
• Natural regulatory T cells are regularly produced from the thymus.
• Induced regulatory T cells are produced on demand in an infection.

Memory T Cells

• Not all activated T cells become T killer/T helper/T regulatory cells.
• Towards the end of an immune response, some cells differentiate into memory cells.
• Memory cells express the same homing receptors as naïve T cells and enter the circulation as immune surveillance.