STEPTRACKERIMMUNOLOGY + GENETICS | CELLS & ORGANS | HIGH-YIELD REVIEW

Lymphocyte Development & Selection

Lymphocytes build a random receptor by cutting and joining gene segments, then are tested — useless ones die, dangerous ones are deleted or silenced.

FOCUS ON

Receptor diversity: VDJ recombination by RAG1/RAG2 (+ Artemis, DNA repair) and junctional diversity (TdT adds N nucleotides); B cells add somatic hypermutation later. T cells (thymus): double-negative → double-positive (CD4⁺CD8⁺) in the cortex → positive selection (bind self-MHC weakly → survive; MHC I → CD8, MHC II → CD4) → negative selection in the medulla (bind self-antigen strongly → apoptosis; AIRE shows tissue antigens) → some become Tregs (FOXP3). B cells (marrow): pro-B → pre-B (μ heavy chain + surrogate light chain) → immature B (IgM) → mature naive B (IgM + IgD); self-reactive B cells undergo deletion, anergy or receptor editing. Defects: RAG → SCID (Omenn), AIRE → APS-1, FOXP3 → IPEX, BTK → XLA.

STEP

WHAT HAPPENS

MOLECULES

DEFECT → DISEASE

VDJ recombination

Gene segments for variable regions cut and joined; ~10¹¹ possible receptors

RAG1/RAG2 (recombinase), Artemis, DNA-PK

RAG/Artemis loss → SCID (T⁻B⁻NK⁺); partial → Omenn syndrome

Junctional diversity

Random nucleotides added at joints

TdT

TdT ⁺ marks lymphoblasts (ALL)

Allelic exclusion

Only one heavy- and one light-chain allele expressed per B cell

—

Each B cell makes one specificity

Pro-T → double-negative

Marrow progenitors enter thymus; CD4⁻CD8⁻

Notch, IL-7 (IL-7R, common γ chain, JAK3)

IL-7R / γc / JAK3 defects → SCID (T⁻B⁺NK⁻ for γc, JAK3)

Double-positive (cortex)

TCR rearranged; CD4⁺CD8⁺

—

Positive selection (cortex)

Thymocytes that bind self-MHC on cortical epithelial cells survive; most die by neglect

MHC I → CD8⁺ · MHC II → CD4⁺

Bare lymphocyte syndrome (no MHC II) → few CD4⁺ cells

Negative selection (medulla)

Strong binding to self-peptide on medullary cells/DCs → apoptosis

AIRE drives expression of tissue-specific antigens

AIRE loss → APS-1 (mucocutaneous candidiasis, hypoparathyroidism, Addison)

Regulatory T cells

Moderately self-reactive cells become Tregs

FOXP3, CD25, IL-2, IL-10, TGF-β

FOXP3 loss → IPEX (enteropathy, diabetes, eczema)

Pro-B → pre-B (marrow)

Heavy chain rearranged first; μ chain pairs with surrogate light chain (pre-BCR)

BTK signaling

BTK loss → XLA (no mature B cells)

Immature B cell

Light chain rearranged; surface IgM; self-reactive cells edited, deleted or made anergic

Receptor editing (new light chain)

Central B-cell tolerance

Mature naive B cell

IgM + IgD (alternative splicing); leaves marrow to follicles

CD19, CD20, CD21

Rituximab targets CD20

Peripheral tolerance

Anergy (signal 1 without B7–CD28), Tregs, deletion (Fas–FasL), immune privilege

CTLA-4, PD-1, Fas

Fas defect → autoimmune lymphoproliferative syndrome

Picture it — thymic selection

Two tests in the thymusIn the cortex, thymocytes that cannot bind self-MHC die; weak binders survive and commit to CD4 or CD8. In the medulla, strong binders to self-peptide are deleted, moderate binders can become Tregs, and the rest leave as naive T cells.

Schematic diagrams, not to scale.

Mechanism — the two thymic tests

No binding to self-MHC

→

Death by neglectUseless

Weak binding

→

Positive selection → surviveCD4 or CD8 chosen

Strong binding to self-peptide

→

Negative selection → apoptosisor Treg

T vs B development

FEATURE

T CELL

B CELL

Site

Thymus

Bone marrow

Receptor

TCR (αβ or γδ)

BCR (surface Ig)

First chain

β chain + pre-Tα

μ heavy chain + surrogate light chain

Self-tolerance

Negative selection (AIRE), Tregs

Deletion, anergy, receptor editing

Later diversity

None

Somatic hypermutation, class switching

How it's tested

COMMON CONFUSIONPositive selection (cortex) tests MHC restriction; negative selection (medulla) tests self-reactivity — the location and the question differ.

THE TRAPAIRE deficiency causes autoimmunity, not immunodeficiency — but chronic Candida appears because of autoantibodies against IL-17/IL-22.

YOUR APPROACHDevelopmental step → gene needed → which cells are missing or self-reactive → resulting disease.

If you see… think…

Enzyme that cuts V, D, J segments → RAG1/RAG2

Enzyme adding random nucleotides, marker of lymphoblasts → TdT

Where positive selection happens → thymic cortex

Where negative selection happens → thymic medulla

Candidiasis + hypoparathyroidism + adrenal failure → AIRE deficiency (APS-1)

Infant boy with diarrhea, diabetes and eczema → IPEX (FOXP3)

Boy with no B cells and absent tonsils → BTK defect (XLA)

Mature naive B cell surface antibodies → IgM and IgD

Self-reactive B cell swaps its light chain → receptor editing

T-cell activation without B7–CD28 → anergy