Adaptive Immunity

Mechanisms, patterns, and what happens when each one fails.

• MHC class I vs class II. MHC I is on ALL nucleated cells (not mature RBCs), presents ENDOGENOUS peptides (viral, tumor) processed by the proteasome and loaded via TAP in the ER, and is read by CD8+ T cells — the rule of 8: 1 × 8 = 8. MHC II is restricted to professional antigen-presenting cells (dendritic cells, macrophages, B cells), presents EXOGENOUS peptides processed in acidified endosomes (invariant chain/CLIP swapped out by HLA-DM), and is read by CD4+ T cells — 2 × 4 = 8.
• T-cell activation needs two signals. Signal 1 = the TCR (with CD4 or CD8) engaging peptide-MHC; signal 2 = costimulation, classically CD28 on the T cell binding B7 (CD80/86) on the APC. Signal 1 without signal 2 produces anergy, not activation — the peripheral-tolerance mechanism exam questions love. CTLA-4 and PD-1 are the inhibitory counterparts (the targets of checkpoint-inhibitor drugs).
• CD4 helper subsets. Th1 (driven by IL-12, secretes IFN-γ) activates macrophages — intracellular pathogens, granulomas, type IV hypersensitivity. Th2 (driven by IL-4, secretes IL-4/IL-5/IL-13) drives IgE class switching and eosinophils — helminths and allergy. Th17 (driven by TGF-β + IL-6, secretes IL-17) recruits neutrophils at mucosal surfaces — extracellular bacteria and fungi. Treg (FoxP3+, CD25+, driven by TGF-β) suppresses via IL-10 and TGF-β — peripheral tolerance.
• CD8 cytotoxic T cells. Kill virus-infected and tumor cells presenting antigen on MHC I, using perforin (pore formation) and granzymes (trigger apoptosis via caspases) plus Fas ligand–Fas engagement. They need help getting licensed — dendritic-cell cross-presentation and CD4 help (IL-2) drive full CTL differentiation.
• The five antibody classes. IgM: first antibody made in a primary response, pentamer in serum, best complement activator, the B-cell receptor as a monomer. IgG: most abundant in serum, dominant in the secondary response, the only class crossing the placenta, opsonizes and fixes complement. IgA: dimer with secretory component at mucosal surfaces and in breast milk. IgE: binds mast cells and basophils via FcεRI — type I hypersensitivity and antihelminth defense. IgD: surface receptor on naive B cells, minimal serum role.
• B-cell activation and class switching. T-dependent responses: the B cell presents antigen on MHC II to a Th cell, receives CD40L–CD40 engagement plus cytokines, and in the germinal center undergoes somatic hypermutation (affinity maturation) and class-switch recombination — the isotype changes (constant region) while specificity (variable region) stays. IL-4 switches to IgE, TGF-β to IgA, IFN-γ toward IgG subclasses. T-independent antigens (polysaccharide capsules) give mostly IgM and poor memory — why conjugate vaccines exist.
• Clonal selection and memory. Each lymphocyte carries ONE antigen specificity, generated before antigen exposure by VDJ recombination (RAG1/RAG2). Antigen selects and expands only the matching clones; some progeny persist as memory cells. This is why the secondary response is faster (days shorter lag), larger, higher-affinity, and IgG-dominant — and it is the entire logic of vaccination and booster doses.
• Central vs peripheral tolerance. Central: in the thymus, positive selection (must weakly recognize self-MHC) then negative selection (strong self-reactivity → deletion; AIRE lets the thymus display peripheral self-antigens — AIRE mutation causes APECED/APS-1). B cells are deleted or receptor-edited in the bone marrow. Peripheral: anergy (signal 1 without 2), Treg suppression, and Fas-mediated deletion. Tolerance failure = autoimmunity.
• Key cytokines to pair with sources. IL-2 — T-cell growth factor (autocrine). IL-12 (from APCs) — drives Th1. IFN-γ (Th1, NK) — activates macrophages, upregulates MHC. IL-4 — drives Th2 and IgE switching. IL-5 — eosinophils and IgA. IL-17 — neutrophil recruitment. IL-10 and TGF-β — suppression. IL-6 — acute phase plus Th17 differentiation. Exam stems test cytokine → source → effect as a three-way match.

Each with the one fact that identifies it. Your course's slides are the authority; use this to check your list against.

1. 1MHC class I — on all nucleated cells; presents endogenous peptide to CD8+ cells
2. 2MHC class II — restricted to professional APCs; presents exogenous peptide to CD4+ cells
3. 3Dendritic cell — the most potent APC; the only one that activates naive T cells
4. 4TAP transporter — pumps proteasome-cut peptides into the ER for class I loading
5. 5Invariant chain (CLIP) — blocks the class II groove until HLA-DM swaps in peptide
6. 6CD28 — the T cell's costimulatory receptor; binds B7 for signal 2
7. 7CTLA-4 — inhibitory receptor that outcompetes CD28 for B7; brake on activation
8. 8Th1 cell — IL-12 induced, secretes IFN-γ; activates macrophages against intracellular microbes
9. 9Th2 cell — IL-4 induced; drives IgE and eosinophils against helminths and in allergy
10. 10Th17 cell — secretes IL-17; recruits neutrophils to mucosal surfaces
11. 11Treg — FoxP3+ CD25+ suppressor; keeps peripheral tolerance via IL-10 and TGF-β
12. 12Perforin and granzymes — the CTL kill mechanism: pore plus caspase-triggered apoptosis
13. 13IgM — pentamer, first responder of the primary response, best complement fixer
14. 14IgG — secondary-response workhorse; the only class that crosses the placenta
15. 15IgA — dimer with secretory component; guards mucosa and rides in breast milk
16. 16IgE — sits on mast cells via FcεRI; type I hypersensitivity and antiparasite defense
17. 17CD40 ligand — the T-helper signal a B cell needs to class-switch; missing in hyper-IgM syndrome
18. 18Somatic hypermutation — germinal-center point mutations that raise antibody affinity
19. 19VDJ recombination — RAG-mediated gene shuffling that builds receptor diversity before antigen
20. 20AIRE — thymic factor displaying peripheral self-antigens for negative selection
21. 21IL-2 — autocrine T-cell growth factor released on activation
22. 22Memory B cell — germinal-center graduate behind the fast, IgG-heavy secondary response

The distinctions that lose points on this material, year after year.

• Swapping the MHC pairings. Under time pressure students match CD4 to class I. Use the multiplication rule — CD4 × MHC II = 8, CD8 × MHC I = 8 — and remember the logic: CD8 cells must survey EVERY nucleated cell for viruses, so class I is everywhere; CD4 cells only need to talk to professional APCs.
• Class switching changes specificity. It does not. Class-switch recombination swaps the heavy-chain CONSTANT region (isotype and effector function); the variable region — and therefore the antigen bound — is unchanged. Affinity changes come from somatic hypermutation, a separate germinal-center process.
• IgM titers read as 'more antibody overall'. A high IgM with low IgG means a RECENT primary exposure; high IgG with low IgM means past infection or vaccination. Serology questions are timing questions — answer them off the primary-vs-secondary curve, not off absolute levels.
• Anergy vs deletion. Signal 1 without costimulation makes the T cell ANERGIC — alive but unresponsive (peripheral tolerance). Deletion by apoptosis is negative selection in the thymus (central tolerance) or Fas-mediated in the periphery. MCQs bait you into calling every tolerance mechanism 'deletion.'
• Natural killer cells filed as adaptive. NK cells are INNATE lymphocytes: no TCR, no VDJ rearrangement, no memory in the classic sense. They kill cells that have LOST MHC I ('missing self') — the exact opposite trigger from CD8 T cells, which require MHC I to kill. A stem about a virus downregulating MHC I is asking for NK cells.
• Polysaccharide antigens and infant vaccines. Pure capsular polysaccharide is T-independent — IgM-heavy, weak in children under 2, no real memory. Conjugating it to a protein carrier recruits T-cell help and germinal centers. 'Why is the vaccine conjugated?' is a class-switching question in disguise.
• Th1/Th2 cross-inhibition forgotten. IFN-γ suppresses Th2 and IL-4/IL-10 suppress Th1 — the subsets antagonize each other. Stems about lepromatous vs tuberculoid leprosy or allergy skew are testing which arm won, not which arm exists.

Where this topic shows up again — in clinic, on rotations, and on the boards.

• Anaphylaxis and allergy (type I). Prior exposure drives Th2-dependent IgE, which arms mast cells via FcεRI; re-exposure cross-links the IgE → immediate degranulation (histamine, tryptase) → urticaria, bronchospasm, hypotension. Mechanistically this is IgE + Th2 + IL-4; treatment is epinephrine first, and serum tryptase is the lab marker.
• TB skin test and contact dermatitis (type IV). Delayed-type hypersensitivity is Th1 memory cells recognizing antigen, releasing IFN-γ, and activating macrophages over 48–72 hours — no antibody involved. The PPD, poison ivy, and granuloma formation are all the same mechanism, which is also why anti-TNF therapy reactivates latent TB.
• Neonatal passive immunity. Maternal IgG crosses the placenta (the only class that does) and protects the infant for roughly the first 6 months; secretory IgA in breast milk covers the gut. This same IgG transfer is what makes Rh disease possible — anti-D IgG from a sensitized mother attacks fetal red cells, while bulky IgM anti-A/anti-B mostly cannot cross.
• X-linked hyper-IgM syndrome. CD40L deficiency on T cells: B cells never get the class-switch signal, so IgM is high or normal while IgG, IgA, and IgE are low. Boys present with recurrent sinopulmonary infections plus Pneumocystis — a pure demonstration that switching requires T-cell help.
• Asplenia and encapsulated organisms. The spleen's marginal zone handles T-independent responses to polysaccharide capsules and clears opsonized organisms. Splenectomized or sickle-cell patients are at risk from Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria — hence pre-splenectomy vaccination against exactly those.
• Transplant rejection. Hyperacute rejection = preformed antibody against donor antigens, within minutes. Acute rejection = recipient T cells (CD8 direct killing, CD4-driven inflammation) over weeks — the target of calcineurin inhibitors, which block IL-2 production. Chronic rejection = years of low-grade cellular and antibody injury with vascular fibrosis.
• Checkpoint inhibitors and their toxicity. Anti-CTLA-4 and anti-PD-1 antibodies release the brakes on tumor-specific T cells. The predictable price is immune-related adverse events — colitis, thyroiditis, hepatitis, pneumonitis — which are iatrogenic autoimmunity, i.e., peripheral tolerance deliberately switched off.
• Serology in practice. IgM-positive means acute or recent infection (it appears in days and fades in weeks-to-months); IgG-positive alone means past infection or immunization. Hepatitis panels, EBV, and prenatal TORCH interpretation all run on this one primary-vs-secondary rule.