Immunology: Lymphocyte Development & Antigen Recognition

🛡️ Antigen receptors: BCR vs TCR

Mature naive lymphocytes each display a single antigen‑binding specificity (idiotype). The B‑cell receptor (BCR) is membrane‑bound immunoglobulin, while the T‑cell receptor (TCR) is a heterodimer that recognises peptide–MHC complexes.

B‑cell receptor (BCR)

Structure: two identical heavy chains + two light chains; disulfide‑linked “Y” shape with a flexible hinge.
Isotypes expressed: IgM and IgD (same idiotype).
Binding: native antigens (proteins, polysaccharides, lipids) – no MHC required.
Signalling: Igα/Igβ (CD79a/b) + co‑receptor CD19/CD21/CD81.
Secreted form: yes, after activation → antibody.

T‑cell receptor (TCR)

Structure: α and β glycoprotein chains; no hinge region → rigid.
Isotypes: single (αβ) per cell.
Binding: peptide fragments presented on MHC molecules.
Signalling: CD3 complex (multichain).
Secreted form: no – always membrane‑anchored.

          ⚡ High‑yield: CD21 (on B cells) is the EBV receptor; CD81 binds HCV and Plasmodium vivax.
        

Feature	BCR	TCR
Molecules per lymphocyte	~100,000	~100,000
Idiotypes per cell	1	1
Isotypes co‑expressed	IgM + IgD	αβ (single)
Secretion	yes	no
Flexibility	flexible hinge	rigid
Signal transducers	Igα/Igβ, CD19, CD21, CD81	CD3

🧩 Generation of receptor diversity

Receptor diversity arises through somatic DNA rearrangements, not from a fixed germline repertoire. Random recombination of V, D, and J segments, plus junctional diversity, creates millions of unique idiotypes.

Heavy chain (B‑cell) / β chain (T‑cell)

V(D)J recombination: select one V, one D, one J from many germline segments.
N‑nucleotide addition by TdT at junctions (active in B‑cell heavy chain and all TCR chains).
RAG1/RAG2 recombinase enzymes catalyse the cuts and joins.

Light chain (B‑cell) / α chain (T‑cell)

VJ recombination (no D segment).
In B cells, TdT is not active during light‑chain rearrangement.
κ or λ constant regions complete the chain.

V→ D→ J→ + N‑nucleotides→ VDJ rearrangement

📌 Clinical correlate – Omenn syndrome / SCID: hypomorphic RAG mutations → partial activity (Omenn: Th2 skew, rash, diarrhoea). Null RAG1/2 → complete B‑ and T‑cell deficiency (SCID).

Allelic exclusion: once a functional heavy (or β) chain is made, rearrangement on the other allele is silenced → one idiotype per cell.
Combinatorial association: any heavy chain can pair with any light chain → multiplies diversity.
Somatic hypermutation occurs in B cells after antigen stimulation (affinity maturation).

🧫 B‑lymphocyte development & selection

B cells mature entirely in the bone marrow (primary lymphoid organ). Development is driven by immunoglobulin gene rearrangements.

Positive selection: survival signals from pre‑BCR and functional Ig.
Negative selection (central tolerance): self‑reactive B cells are deleted (clonal deletion) or rendered anergic (high IgD, low IgM).
Stromal cells and macrophages in the bone marrow present self‑antigens to delete high‑affinity autoreactive clones.

⚠️ Anergic B cells: express high surface IgD and are functionally unresponsive in the periphery.

Key enzymes and markers

TdT – terminal deoxynucleotidyl transferase; adds N‑nucleotides; used as a marker in acute lymphoblastic leukemia (ALL).
RAG1/RAG2 – essential for V(D)J recombination; defects cause severe combined immunodeficiency.

          ✅ Clinical pearl: failure of rearrangement on both homologous chromosomes triggers apoptosis – this ensures only functional lymphocytes survive.
        

🧪 T‑lymphocyte development & thymic selection

Pre‑T cells migrate from bone marrow to the thymus (cortex → medulla). They undergo two selection checkpoints.

Double‑negative (DN)

No CD4 or CD8; TCR β‑chain rearranges first.

Double‑positive (DP)

Express CD4, CD8, and TCR αβ; located in cortex.

Positive selection

TCR binds self‑MHC with low affinity → survival; otherwise apoptosis.

Negative selection

High‑affinity binding to self‑peptide:MHC → apoptosis (clonal deletion) or Treg differentiation.

Lineage commitment

TCR → class I MHC → CD8⁺ cytotoxic T cell.
TCR → class II MHC → CD4⁺ helper T cell.

Regulatory T cells (Tregs)

CD25⁺ FoxP3⁺; secrete IL‑10 and TGF‑β.
Suppress self‑reactive Th1 cells; critical for peripheral tolerance.

🔥 95–99% of thymocytes die during selection – only cells with useful, non‑autoreactive TCRs exit to the periphery.

🧬 MHC (HLA) molecules – peptide presentation

MHC molecules are highly polymorphic cell‑surface glycoproteins that present peptide antigens to T cells.

Class I MHC (HLA‑A, ‑B, ‑C)

Expressed on all nucleated cells and platelets.
Heavy chain (α) + β₂‑microglobulin (not MHC‑encoded).
Presents intracellular (endogenous) peptides to CD8⁺ T cells.

Class II MHC (HLA‑DP, ‑DQ, ‑DR; also HLA‑DM chaperone)

Expressed on professional APCs: dendritic cells, macrophages, B cells.
α and β chains of similar length; peptide‑binding groove at N‑terminus.
Presents extracellular (exogenous) peptides to CD4⁺ T cells.

          🧪 HLA‑DM is not a surface molecule; it acts as a chaperone to facilitate peptide loading onto class II.
        

💡 Clinical pearls & high‑yield facts

RAG mutations: Omenn syndrome (partial activity, Th2, rash, diarrhoea) vs. null → SCID (no B/T cells).
TdT: expressed during early lymphocyte development; marker for T‑ALL and B‑ALL.
CD21 = complement receptor 2 (CR2) and EBV receptor.
CD81 = receptor for HCV and P. vivax.
Class I MHC presents viral/neoantigens to CD8⁺ CTLs; class II presents bacterial/extracellular antigens to CD4⁺ helpers.
FoxP3 is the master transcription factor for Tregs; its deficiency causes IPEX syndrome.

📖 Exam tip: “Allelic exclusion” ensures each lymphocyte has one receptor specificity. “Somatic hypermutation” (B cells only) increases affinity after antigen exposure.

Multiple V, D, J segments – inherited diversity.
VDJ recombination – combinatorial joining.
N‑nucleotide addition – TdT adds random bases.
Combinatorial association – heavy/light (or α/β) chain pairing.
Somatic hypermutation – point mutations in B cells after antigen encounter.

Generated in thymus from self‑reactive precursors.
Constitutively express CD25 (IL‑2Rα) and FoxP3.
Suppress effector T cells via IL‑10 and TGF‑β.
Deficiency → autoimmune disease (IPEX).

🛡️ Antigen receptors: BCR vs TCR −