BMS 150 Week 4: T-Cell Development and Tolerance

T-cell Development and Tolerance

• T-cell development occurs in the bone marrow and thymus
• Stem cells differentiate into lymphoid progenitors under the influence of IL-7
• T-cells undergo little maturation in the bone marrow and need to travel to the thymus to develop functional T-cell receptors (TCRs)

The Thymus

• Located superior to the heart, anterior to the great vessels
• Largest prior to puberty, shrinks afterwards
• Divided into a cortex and medulla, surrounded by a thin capsule
• Medullary and cortical thymic epithelial cells (mTEC and cTEC) guide T-cell development

Thymic T-cell Development

• Precursor T-lymphocytes undergo terminal differentiation to T-lymphocyte lineage
• Rearrange TCR and learn to recognize antigen presented via HLA (HLA restriction)
• T-cells with TCRs that bind to antigen presented via HLA survive (positive selection)
• T-cells that bind to self-antigen with high affinity are eliminated (negative selection)
• Selected to express either CD4 or CD8

T-cell Development - Selection

• Positive selection: DP T-cells that have arranged their TCR with low-medium affinity for thymic epithelial cells' HLA-bound self-antigen survive
• Negative selection: DP T-cells that have arranged their TCR with high affinity for thymic epithelial cells' HLA-bound self-antigen are eliminated

Peripheral vs. Central Tolerance

• Central tolerance: occurs in primary lymphoid organs with negative selection
• Peripheral tolerance: occurs in secondary lymphoid organs or peripheral tissue

Central Tolerance

• AIRE gene plays a central role in central tolerance
• AIRE activates transcription factors, causing thymic epithelial cells to express a wide range of proteins on their HLA
• Defects in AIRE result in autoimmune polyendocrinopathy syndrome (APS)

Peripheral Tolerance

• CD4+ Treg cells: polarized by interaction with APC and high circulating levels of TGF-β
• CTLA-4: expressed by helper T-cells, binds to B7 with higher affinity than CD28, and can cause anergy or Treg polarization
• T-reg cells often express CTLA-4, shutting down CD80/86 expression on APCs

Lymphatic System

• Lymphatic capillaries: driven by interstitial fluid build-up on the outside of capillaries, which puts pressure on the capillary cells and forces them apart
• Lymphatic flow in larger channels: driven by contraction of skeletal muscle surrounding lymphatic vessels and pressure created through breathing

Lymphatic Anatomy

• Lymph vessels combine to form trunks, which combine to form one of two lymphatic ducts that drain into the blood system
• Right lymphatic duct drains the right arm, thoracic region, and right head/neck into the juncture of the right subclavian vein and right internal jugular
• Thoracic duct drains the rest of the body into the juncture of the left subclavian vein and left internal jugular

Here are the study notes:

Lymphocyte Development and Immune Tolerance

• Lymphocyte development occurs in the bone marrow, where stem cells differentiate into lymphoid progenitors under the influence of IL-7.
• T-cells, unlike B-cells, undergo little maturation in the bone marrow and need to travel to the thymus to develop functional T-cell receptors (TCRs).

The Thymus

• The thymus is a key organ in T-lymphocyte development, where precursor T-lymphocytes:
  • Become terminally differentiated to the T-lymphocyte lineage
  • Rearrange the TCR
  • "Learn" to recognize antigen presented via HLA (HLA restriction)
  • "Learn" to ignore self-antigens presented via HLA
  • Are selected to express either CD4 or CD8

T-cell Development

• Positive selection: DP T-cells with low-medium affinity for thymic epithelial cell HLA bound to self-antigen are allowed to survive.
• Negative selection: DP T-cells with high affinity for thymic epithelial cell HLA bound to self-antigen are killed.

Central Tolerance

• Central tolerance occurs in primary lymphoid organs, such as the thymus, and involves negative selection to eliminate self-reactive T-cells.

Peripheral Tolerance

• Peripheral tolerance involves the generation of regulatory T-cells (Tregs) that suppress autoreactive T-cells.
• Tregs are polarized by interaction with an APC and high circulating levels of TGF-β.

Barrier Tolerance

• Barrier tolerance occurs in mucosal surfaces, where secreted IgA reduces invasion of microbes and TGF-β promotes class-switching to IgA by B-cells.

Genes Implicated in Decreased Tolerance and Autoimmunity

• IL-2R-alpha and CTLA4 are key genes implicated in decreased tolerance and autoimmunity.

Central Tolerance in B-cells

• Central tolerance in B-cells involves the elimination of self-reactive B-cells through receptor editing and clonal deletion.

The Spleen

• The spleen is a secondary lymphoid organ where immature B-cells mature and undergo negative selection.
• The spleen has a key role in immune responses to antigens in the bloodstream.
• The spleen is composed of white pulp (surrounds arterioles) and red pulp (peripheral to the white pulp).

Lymphatic System

• The lymphatic system provides the driving force for lymph to enter lymph capillaries through interstitial fluid build-up on the outside of the capillaries.
• Contraction of skeletal muscle surrounding the lymphatic vessels and pressure created through breathing facilitate lymph circulation in larger lymphatic vessels.