T Cell Development and Thymic Selection

Flashcards covering Lecture 13 notes on T cell development, thymic anatomy, lineage commitment, receptor gene rearrangement checkpoints, and positive and negative selection.

Lymph Node

A secondary lymphoid organ where mature, naïve $T$ cells reside and become activated by dendritic cells before migrating into peripheral tissue.

T Cell

A lymphocyte whose name stands for 'Thymus cell,' indicating the primary organ where precursor cells mature into naïve $T$ cells.

Hematopoietic Stem Cell Progenitors

Progenitor cells residing in the bone marrow that differentiate into $T$ cell precursors prior to migration to the thymus.

Naïve T Cells

Mature $T$ cells that have completed development in the thymus and migrated to secondary lymphoid tissues (such as lymph nodes, spleen, and GALT) awaiting antigen activation.

Autoimmune Responses

Adaptive immune responses inappropriately mounted against self-proteins, which can cause diseases such as type 2 diabetes or lupus.

Thymocyte

A developing $T$ cell of bone marrow origin that matures inside the thymus.

Thymus

The specialized immune organ enclosed by a capsule and divided into an outer cortex and an inner medulla, serving as the site of $T$ cell maturation and selection.

DiGeorge Syndrome

A developmental disease affecting approximately $1\text{ in }\sim 4000$ people that impacts multiple organs and is characterized by the congenital absence of a thymus and a complete lack of mature $T$ cells.

Nude Mouse

A severely immunocompromised albino mouse strain discovered in Glasgow that has no thymus and no $T$ cells.

FOXN1

A gene required for thymus development that carries a mutation in nude mice, preventing thymic organogenesis.

Neonatal Thymectomy

The surgical removal of the thymus in newborn mice, which completely eliminates the generation of $T$ cells.

Adult Thymectomy

The surgical excision of the thymus from an adult animal, which does not eliminate existing $T$ cells because a sufficient repertoire has already been produced.

Thymic Involution

The progressive shrinking of the thymus over time where functional thymic tissue is replaced by fat, leading to an age-associated decline in the production of new $T$ cells.

CD3

A lineage-defining surface marker absent on uncommitted progenitors entering the thymus ($\text{CD3}^-$) but expressed by all thymocytes once they commit to the $T$ cell lineage ($\text{CD3}^+$).

Double-Negative (DN) Thymocytes

Developing thymocytes that express $\text{CD3}$ but lack both $\text{CD4}$ and $\text{CD8}$ ($\text{CD3}^+\text{CD4}^-\text{CD8}^-$).

Double-Positive (DP) Thymocytes

Intermediate developing thymocytes that express both coreceptors alongside $\text{CD3}$ ($\text{CD3}^+\text{CD4}^+\text{CD8}^+$).

Single-Positive (SP) Thymocytes

Late-stage thymocytes that express $\text{CD3}$ and have committed to expressing only one coreceptor: either $\text{CD4}^+\text{CD8}^-$ (helper) or $\text{CD4}^-\text{CD8}^+$ (cytotoxic).

RAG Genes (RAG-1 and RAG-2)

Recombinase genes upregulated by committed thymocytes that mediate $VDJ$ gene rearrangement to assemble a functional TCR.

Thymic Medulla

The inner compartment of the thymus where progenitor $T$ cells enter via blood venules to proliferate, and where thymocytes return for negative selection.

Subcapsular Region

The peripheral cortical zone of the thymus toward which committed double-negative thymocytes migrate as they rearrange their $\beta$-chain genes.

$\alpha\beta$ T Cells

The predominant $T$ cell population, comprising $\sim 95\%$ of all $T$ cells, that express an antigen receptor formed by $\alpha$ and $\beta$ chains.

$\gamma\delta$ T Cells

A distinct subset of $T$ cells found primarily at mucosal sites like the intestines, which mostly remain $\text{CD4}/\text{CD8}$ double negative, exhibit limited diversity, detect cellular stress molecules, and function similarly to innate immune cells.

Pre-TCR

A transient receptor complex formed by a newly rearranged $\beta$ chain paired with an invariant surrogate $\alpha$ chain ($p\text{T}\alpha$).

Surrogate $\alpha$ Chain ($p\text{T}\alpha$)

An invariant placeholder polypeptide assembled with a rearranged $\beta$ chain to test $\beta$-chain signaling before $\alpha$-chain rearrangement takes place.

First Thymocyte Checkpoint

A developmental evaluation testing whether the rearranged $\beta$ chain forms a signaling pre-TCR; functional signaling halts further $\beta$ rearrangement, induces proliferation, and initiates $\text{CD4}$ and $\text{CD8}$ expression.

Frameshift Mutation

The most common genetic error occurring during $VDJ$ recombination that alters the reading frame, producing premature stop codons and truncated, non-functional receptor chains.

Death by Neglect

Apoptotic cell death that occurs when a thymocyte fails to generate a functional receptor or fails to receive survival signals during positive selection.

Second Thymocyte Checkpoint

A developmental checkpoint where the newly rearranged $\alpha$ chain replaces the surrogate $\alpha$ chain to assemble a complete $\alpha\beta$ TCR and is evaluated for signaling.

Positive Selection

The selection event mediated by cortical epithelial cells where thymocytes that bind self-MHC class I or class II with moderate or strong affinity receive a positive survival signal, while non-binding cells die by neglect.

Development of early alpha-beta T cells in the thymus pathway

1. Medulla (triple negative) - progenitor T cells enter the medulla from the blood and proliferate

2. thymocytes commit to T cell lineage (double negative) - move to the cortex and do VDJ recombination

3. check if Beta chain works once it rearranges (use surrgote alpha)

4. thymocytes start rearranging their alpha chain (V+J) - double positive & back in the medulla as it replaces the surgote alpha

where do double negative T cells proliferate

Sub-capsullar region in the thymus

Thymic Cortical Epithelial Cells

Stromal cells of thymic origin located in the cortex that present self-peptides on MHC class I and II to mediate positive selection.

Practice Peptides

Self-peptides generated and displayed on MHC molecules by thymic cortical epithelial cells to scan and test thymocyte MHC-binding capacity.

CD4 Lineage Commitment

The developmental outcome where a double-positive thymocyte whose TCR recognizes self-peptide presented on MHC class II downregulates $\text{CD8}$ to become a $\text{CD4}^+$ single-positive helper $T$ cell.

CD8 Lineage Commitment

The developmental outcome where a double-positive thymocyte whose TCR recognizes self-peptide presented on MHC class I downregulates $\text{CD4}$ to become a $\text{CD8}^+$ single-positive cytotoxic $T$ cell.

Thymic Stromal Cells

Non-immune cells of thymic origin—specifically cortical and medullary epithelial cells—that constitute the structural architecture of the thymus and regulate selection.

Bone Marrow Chimera

An experimental animal model created by lethally irradiating a host to ablate endogenous bone marrow progenitors and reconstituting it with donor bone marrow, yielding stromal cells of one genotype and immune cells of another.

Radiation Sensitivity of Bone Marrow Progenitors

The physiological susceptibility of hematopoietic stem and progenitor cells to radiation, exploited to eliminate host immune cells while preserving radioresistant thymic stromal cells.

Thymic Medullary Epithelial Cells (MECs)

Stromal cells of thymic origin in the medulla that express the transcription factor AIRE and participate in negative selection.

Autoimmune Regulator (AIRE)

A transcription factor expressed in thymic medullary epithelial cells that drives the ectopic expression of peripheral tissue-specific proteins to enable central tolerance.

Clonal Deletion

The apoptotic elimination of autoreactive thymocytes that bind self-peptide:MHC complexes with high affinity during negative selection.

Negative Selection

The thymic process—primarily mediated by bone-marrow-derived dendritic cells and macrophages and minorly by MECs—that deletes self-reactive thymocytes to ensure self-tolerance.