Chapter 5: T Cell Development

Thymic Epithelial Cells

support thymocyte development and participate in important checkpoints

Macrophages

remove dead thymocytes

Dendritic Cells

present self-peptides (antigens from self) and MHC to developing thymocytes to check for functional chain and self-tolerance

Hassall’s (thymic) Corpuscles

contain cells that instruct a subset of thymocytes to become regulatory T cells (Treg)

Notch Signaling Pathway

stimulated by a cell surface receptor that interacts with transmembrane ligands on adjacent cells; Notch from cleaved receptor regulates cell proliferation and differentiation

Notch Signaling Pathway: Double Negative Thymocyte

does not express CD4 or CD8 during initial development; begins development in cortex, begins somatic recombination at the TCR loci and continues until both subunits of the receptor have properly rearranged in order for CD4 and CD8 to express

Notch Signaling Pathway: Double Positive Thymocyte

express a fully rearranged TCR, CD4 and CD8; some develop into regulatory T cells, some into NK cells, other begin positive and negative selection to test the TCR and select a single coreceptor to become a single-positive thymocyte

Development T Cell Checkpoints

γδ checkpoints, Beta checkpoints, alpha checkpoint

yo checkpoint

protect the fetus during development, protect mucosal surfaces in adults

Beta checkpoint

developing thymocyte must assemble a TCR complex, Pre-T alpha chain (pTa) assembles with the rearranged beta chain and CD3 complex to form the pre-TCR, ensures that a functioning TCR can signal via the same transduction pathways used to activate T cells

After Beta checkpoint

the cell proliferates and expresses RAG1 and RAG2 again, begins recombination at the other TCR loci (alpha, gamma, delta), undergoes allelic exclusion, chains arise from a single allele

Alpha Checkpoint

recombination of a-chain locus occurs after beta checkpoint has passed

Positive Selection Thymocytes

promotes the selection of thymocytes that can bind to self-MHC molecules (MHC restriction), selection within the thymic cortex; developing thymocytes with TCRs that can interact with an MHC-peptide complex with a low or intermediate affinity survive and proliferate

PS: Thymocytes, Selection within the Thymic Cortex

developing thymocytes interact with cortical thymic epithelial cells (cTECs) to test the affinity of the TCR with MHC-self peptide complexes at cell surface

Negative Selection Thymocytes

prevents the release of thymocytes that can recognize MHC self peptide complexes with high affinity, selection within the thymic medulla; developing thymocytes can bind too tightly to an MHC peptide complex

NS: Selection within the Thymic Medulla, Central Tolerance

negative selection processes that occur in primary lymphoid tissues that responsible for the removal of self-reactive lymphocyte

AIRE

a transcriptional activator, autoimmune regulator; allows cells to express genes not normally expressed by epithelial cells of the thymus, promiscuous gene expression