2-5 T Cell Development

Question 1

What is the cellular composition of the thymus?

Answer 1

• Organized into cortex and medulla, with a cortico-medullary junction between them
• Cortex: immature thymocytes, branched cortical epithelial cells, macrophages
• Medulla: mature thymocytes, medullary epithelial cells, dendritic cells, macrophages; characteristic Hassall’s corpuscles
• Macrophages in both cortex and medulla remove the many thymocytes that fail to mature properly

Question 2

How does the thymus change over a person’s lifetime?

Answer 2

Beginning with birth, the T cell-producing tissue of the thymus is gradually replaced by fatty tissue (involution of the thymus), and thymus function declines. Thymectomy does not appear to impair T-cell immunity significantly; once established, the repertoire of mature peripheral T cells seems to be long lived, self-replenishing, or both.

Question 3

Where are T cells originally from, and where do they end up?

Answer 3

T cell precursors are the products of bone marrow stem cells; they travel to and develop in the thymus.

After maturation, T cells leave the thymus for the secondary lymphoid organs: lymph nodes, spleen, gut-associated lymph tissue (GALT).

Question 4

What are the major T-cell subsets within the thymus?

Answer 4

T-cell precursor → α:β T cells (majority) + γ:δ T cells (minority)

α:β T cells → CD4 (recognizes peptide antigens presented by MHC class II) + CD8 (recognizes peptide antigens presented by MHC class I)

Question 5

What are the stages of T-cell development?

Answer 5

• Cell surface markers can be used to identify stages of T-cell development
• Uncommitted progenitor cells, which express stem-cell surface marker (CD34) and adhesion (CD44) glycoproteins → double-negative thymocytes committed to the T-cell lineage
• Developing T cells are in close contact with the thymic epithelium, which introduces them to antigens

Question 6

What is the overall scheme of lineage commitment in T cells?

Answer 6

Essentially, the γ and δ loci compete with the β locus in double-negative committed T-cell precursors in a race to make functional T-cell receptor chains. Even after that particular “race,” rearrangements continue. Cells that fail to make productive T-cell receptor rearrangements apoptose and are phagocytosed by cortical macrophages.

Question 7

How can T-cell gene rearrangements generate different receptors?

Answer 7

• γ:δ T receptor assembles and γ:δ T cell leaves thymus
• OR β receptor assembles first (favored, because only 1 rearrangement required and 2 attempts allowed per chromosome), followed by . . .
• 1st checkpoint: functional β chain can bind α chain → pre-T cell receptor
• The α-chain locus can sustain several attempts at productive rearrangement, but the linked δ chain gets spliced out irreversibly
• 2nd checkpoint: α chain can bind a β chain and assemble a T-cell receptor → positive selection

The same RAG enzymes are used as in B cells.

Question 8

What are positive and negative T cell selection?

Answer 8

Positive selection

• In cortical epithelial cells of thymus (both MHC class I and class II molecules)
• Double-positive (CD4+CD8) α:β T cells with moderate/strong binding to self-MHC molecules → single-positive CD4 or CD8 α:β T cells

Negative selection

• In dendritic cells, macrophages, and other cells in thymus
• Double-positive α:β T cells with tight binding to self-MHC/-peptides (potentially autoreactive) → apoptosis
• Process by which T cells become self-tolerant

Question 9

What is the avidity model of T-cell selection?

Answer 9

• Depends on the affinity of the TCR-peptide/MHC interaction + the density of the peptide/MHC on the thymic epithelial cell (i.e., the avidity)
• More avidity → more intense signal