Adaptive Immunity — T & B Cells

Adaptive (acquired) immunity is the antigen-specific, memory-generating arm of the immune system, mediated by lymphocytes. T cells drive cell-mediated immunity while B cells drive humoral immunity. This topic underpins immunodeficiency, hypersensitivity, transplant and vaccine questions in NEET PG.

Innate vs Adaptive — the foundation

Before lymphocyte detail, anchor the two arms. The key distinguishing feature of adaptive immunity is specificity, diversity, and immunological memory.

Feature	Innate immunity	Adaptive immunity
Specificity	Broad (PAMPs via PRRs)	Highly specific (unique epitopes)
Memory	Absent	Present (memory cells)
Receptors	Germline-encoded (TLRs, NLRs)	Somatically rearranged (TCR, BCR)
Diversity	Limited	Enormous (V(D)J recombination)
Response time	Immediate (hours)	Delayed (days, faster on re-exposure)
Key cells	Neutrophils, macrophages, NK, dendritic	T lymphocytes, B lymphocytes

High-yield: The receptor diversity of T and B cells is generated by V(D)J recombination, mediated by the enzymes RAG-1 and RAG-2 (recombination-activating genes). Defective RAG → SCID (Omenn syndrome with hypomorphic mutations).

Lymphocyte development & maturation

• T cells mature in the thymus (thymic education).
• B cells mature in the bone marrow (in humans; in birds, the bursa of Fabricius — hence "B" cell).

Thymic selection flow: Positive selection (cortex) → Negative selection (medulla) → mature naïve T cell exits

1. Positive selection — thymocytes that can bind self-MHC with low affinity survive (ensures MHC restriction). Failure to bind → death by neglect.
2. Negative selection — thymocytes binding self-peptide–MHC with high affinity are deleted (central tolerance). The transcription factor AIRE drives ectopic expression of tissue-specific antigens in medullary thymic epithelial cells.

High-yield: Mutation in AIRE → APECED / APS-1 (autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy). FoxP3 mutation → IPEX syndrome (failure of Treg-mediated peripheral tolerance).

T-cell subsets & CD markers

All T cells express CD3 (the signal-transducing complex of the TCR). The TCR itself recognises peptide presented on MHC — naked antigen is not recognised (MHC restriction).

Subset	Key marker	MHC restriction	Principal function
Helper T (Th)	CD4	MHC class II	Cytokine help, coordinate response
Cytotoxic T (CTL)	CD8	MHC class I	Kill virus-infected/tumour cells
Regulatory T (Treg)	CD4 CD25 FoxP3	MHC II	Suppress immune response (tolerance)
NKT	CD1d-restricted	CD1d (lipid)	Bridge innate/adaptive
γδ T cells	TCR γδ	Non-classical	Mucosal/epithelial surveillance

The Rule of 8: CD8 recognises MHC class I (8 = 8×1), CD4 recognises MHC class II (8 = 4×2). A reliable exam memory aid.

High-yield: MHC class I (HLA-A, B, C) presents endogenous (cytosolic/viral) antigens to CD8 cells. MHC class II (HLA-DP, DQ, DR) presents exogenous (phagocytosed) antigens to CD4 cells. Class I is on all nucleated cells; class II only on professional APCs (dendritic cells, macrophages, B cells).

CD4 T-helper subsets — the most tested table

Naïve CD4 T cells differentiate based on the cytokine milieu set by the innate response. This is a frequently asked correlation.

Subset	Inducing cytokine	Master TF	Signature cytokines	Defends against	Disease link
Th1	IL-12, IFN-γ	T-bet	IFN-γ, IL-2	Intracellular bacteria, viruses	Activates macrophages; granuloma (TB)
Th2	IL-4	GATA-3	IL-4, IL-5, IL-13	Helminths	Allergy, asthma; IgE/eosinophils
Th17	TGF-β + IL-6, IL-23	RORγt	IL-17, IL-22	Extracellular bacteria, fungi	Psoriasis, RA, MS; neutrophil recruitment
Treg	TGF-β (alone), IL-2	FoxP3	IL-10, TGF-β	—	Self-tolerance; loss → autoimmunity
Tfh	IL-6, IL-21	Bcl-6	IL-21	Helps B cells	Germinal centre help

High-yield: IL-12 is the pivotal Th1-driving cytokine (produced by dendritic cells/macrophages). Defect in IL-12 / IL-12 receptor or IFN-γ receptor → Mendelian susceptibility to mycobacterial disease (MSMD) — disseminated BCG/atypical mycobacterial infection.

High-yield: Th17 cells are central to defence against extracellular fungi (Candida) and bacteria. Hyper-IgE (Job) syndrome (STAT3 mutation) impairs Th17 → recurrent cold staphylococcal abscesses, eczema, retained primary teeth, high IgE.

T-cell activation — the two-signal model

Naïve T-cell activation requires TWO signals; signal 1 alone causes anergy (a tolerance mechanism).

Signal 1 → Signal 2 → Signal 3 (cytokines) → clonal expansion & differentiation

1. Signal 1: TCR–CD3 engages peptide–MHC on the APC (with CD4/CD8 co-receptor).
2. Signal 2 (co-stimulation): CD28 on T cell binds B7 (CD80/CD86) on the APC.
3. Signal 3: cytokines (e.g., IL-12) determine the effector lineage.

Checkpoint regulation (high-yield for immunotherapy):

• CTLA-4 (CD152) competes with CD28 for B7 with higher affinity → inhibitory. Target of ipilimumab. Abatacept (CTLA4-Ig) is therapeutic immunosuppression.
• PD-1 / PD-L1 delivers an inhibitory signal in peripheral tissues. Targeted by nivolumab, pembrolizumab (anti-PD-1) and atezolizumab (anti-PD-L1) in cancer immunotherapy.

High-yield: Without co-stimulation (signal 2), the T cell becomes anergic — a key mechanism of peripheral tolerance. This is why blocking co-stimulation (abatacept) is immunosuppressive.

Cytotoxic T cells (CTL) — killing mechanisms

CD8 CTLs kill via:

1. Perforin–granzyme pathway — perforin polymerises pores; granzyme B enters and activates caspases → apoptosis.
2. Fas–FasL (CD95) pathway — engages the extrinsic apoptotic cascade.

High-yield: Defective perforin/granzyme degranulation → Familial Haemophagocytic Lymphohistiocytosis (HLH) and Chediak–Higashi / Griscelli syndromes. The cytotoxic machinery also underlies NK-cell killing.

B cells & humoral immunity

B cells express surface immunoglobulin (BCR) as their antigen receptor and serve dual roles: antibody production and antigen presentation (MHC II positive).

Antigen types

• Thymus-dependent (TD) antigens: proteins; require T-cell help; produce memory + class switching + high affinity antibodies.
• Thymus-independent (TI) antigens: polysaccharides, LPS; activate B cells directly (cross-link BCR); produce mainly IgM, no memory.

High-yield: Infants <2 years respond poorly to TI polysaccharide antigens — hence conjugate vaccines (Hib, pneumococcal, meningococcal) link polysaccharide to a protein carrier to recruit T-cell help and generate memory.

Germinal centre reaction — the core of high-affinity humoral immunity

When a B cell encounters a TD antigen and receives help from a Tfh cell (via CD40L–CD40 interaction), it enters the germinal centre of the lymph node follicle.

Antigen capture → T-B cooperation (CD40L–CD40) → germinal centre formation → somatic hypermutation + affinity maturation (dark zone) → selection (light zone) → class switching → plasma cell / memory B cell

Two structural zones:

• Dark zone: rapidly dividing centroblasts undergo somatic hypermutation.
• Light zone: centrocytes are selected for high affinity by follicular dendritic cells and Tfh cells.

Process	Enzyme/molecule	Result
Somatic hypermutation	AID (activation-induced cytidine deaminase)	Point mutations in variable region → affinity maturation
Class switch recombination (CSR)	AID + CD40L–CD40 + cytokines	IgM → IgG/IgA/IgE (constant region change)
V(D)J recombination	RAG-1/2	Initial BCR/TCR diversity

High-yield: AID deficiency and CD40L (CD154) deficiency both cause Hyper-IgM syndrome — high/normal IgM, low IgG/IgA/IgE, no germinal centres, susceptibility to Pneumocystis jirovecii and Cryptosporidium. CD40L deficiency is X-linked; AID deficiency is autosomal recessive.

High-yield: Cytokines steer class switching — IL-4 → IgE/IgG (Th2), TGF-β → IgA, IFN-γ → IgG (opsonising). IL-5 promotes eosinophils and IgA.

Plasma cells vs memory B cells

• Plasma cells: terminally differentiated antibody factories; CD138 positive, lose surface Ig and MHC II; long-lived ones reside in bone marrow.
• Memory B cells: persist, mount rapid high-affinity IgG secondary responses.

Primary vs secondary antibody response

Feature	Primary response	Secondary response
Lag phase	Long (5–10 days)	Short (1–3 days)
Predominant Ig	IgM	IgG
Magnitude	Lower	Much higher (memory)
Affinity	Lower	High (affinity-matured)
Antigen dose needed	High	Low

High-yield: IgM indicates acute/recent infection (also the first Ig in ontogeny and the first produced in a response). IgG indicates past infection/immunity and is the only Ig crossing the placenta. Detection of IgM in neonatal serum suggests intrauterine (congenital) infection since IgM does not cross the placenta.

Key immunodeficiencies (T vs B defects)

A favourite NEET PG integration point — localise the defect.

Disorder	Defect	Arm affected	Clue
X-linked agammaglobulinaemia (Bruton)	BTK; B-cell maturation arrest	B cell (humoral)	Boys, absent B cells, recurrent pyogenic infection after 6 mo, absent tonsils
Selective IgA deficiency	—	Humoral	Most common 1° immunodeficiency; anaphylaxis to blood products
CVID	Variable	Humoral	Adult onset, low Ig, autoimmunity, lymphoma risk
DiGeorge	22q11 del; thymic aplasia	T cell	Hypocalcaemia, cardiac, facial; CATCH-22
SCID	IL-2Rγ (X-linked), ADA, RAG	Both	"Bubble boy," failure to thrive, no thymic shadow
Hyper-IgM	CD40L / AID	Class switch	High IgM, low IgG; PCP, Cryptosporidium
Wiskott–Aldrich	WAS gene	Both	Eczema, thrombocytopenia (small platelets), infections
Ataxia-telangiectasia	ATM	Both	Ataxia, telangiectasia, low IgA, radiosensitivity

High-yield: B-cell defects present after ~6 months (maternal IgG wanes) with recurrent encapsulated bacterial infections. T-cell defects present earlier with viral, fungal, and opportunistic (PCP) infections. Combined defects → both.

Mnemonic for SCID causes: Most common is X-linked (IL-2 receptor common γ-chain); autosomal recessive most common is ADA (adenosine deaminase) deficiency.

Cytokines you must memorise

• IL-1, IL-6, TNF-α — pyrogenic, acute phase (IL-6 → CRP).
• IL-2 — autocrine T-cell growth factor.
• IL-4 — Th2, IgE class switch.
• IL-5 — eosinophils.
• IL-10, TGF-β — anti-inflammatory (Treg).
• IL-12 — Th1 induction (from APC).
• IFN-γ — macrophage activation (Th1 signature).
• IL-17/IL-23 axis — Th17, neutrophils, autoimmunity.

Recently asked / exam angle

• Two-signal model & co-stimulation: Direct questions on CD28–B7, CTLA-4 (target of ipilimumab), PD-1/PD-L1 immunotherapy. Match the drug to its checkpoint target.
• Th subset–master transcription factor pairing: Th1–T-bet, Th2–GATA3, Th17–RORγt, Treg–FoxP3, Tfh–Bcl6. Asked as direct matching MCQs.
• AIRE → APECED and FoxP3 → IPEX — central vs peripheral tolerance question.
• Hyper-IgM = CD40L/AID; germinal centre and class switch defect — clinical vignette with PCP/Cryptosporidium.
• Rule of 8 / MHC restriction — endogenous (MHC I, CD8) vs exogenous (MHC II, CD4) antigen presentation pathways.
• AID & RAG functions — somatic hypermutation/class switch (AID) vs V(D)J recombination (RAG). Frequently swapped as distractors.
• Conjugate vaccine rationale — converting TI polysaccharide into TD response.
• Localising immunodeficiency — onset timing and infection type (Bruton vs DiGeorge vs SCID).
• IL-12/IFN-γ axis defect → disseminated mycobacterial/BCG disease (MSMD).

Rapid revision

1. T cells mature in thymus; B cells in bone marrow (bursal equivalent).
2. Positive selection = survival of self-MHC binders (cortex); negative selection = deletion of self-reactive clones (medulla, AIRE-driven).
3. Rule of 8: CD8 → MHC I (endogenous), CD4 → MHC II (exogenous).
4. Two signals for T-cell activation: TCR–peptide/MHC + CD28–B7; signal 1 alone → anergy.
5. CTLA-4 = inhibitory (ipilimumab, abatacept); PD-1/PD-L1 = nivolumab/pembrolizumab/atezolizumab.
6. Th master TFs: T-bet, GATA3, RORγt, FoxP3, Bcl6.
7. IL-12 → Th1 → IFN-γ → macrophage activation; defect → disseminated mycobacteria.
8. AID = somatic hypermutation + class switch; RAG = V(D)J recombination.
9. CD40L–CD40 drives germinal centre, class switch; defect → Hyper-IgM (X-linked).
10. Primary response = IgM; secondary = IgG (memory, high affinity). Only IgG crosses placenta; neonatal IgM = congenital infection.
11. Conjugate vaccines convert TI polysaccharide antigens into memory-generating TD responses.
12. Plasma cell = CD138+; Treg = CD4 CD25 FoxP3; all T cells = CD3+.