Immune Response (Cell-mediated and Antibody-mediated)

Two Arms

CMI: destroys intracellular-microbe-carrying cells + tumor cells. Effector: cytotoxic T cell (main), NK cells, macrophages. AMI: antibodies vs extracellular/surface microbes. No role once organism is intracellular.

TH Cell Activation (3 signals)

1. Antigen-specific: MHC-II-peptide (APC) + TCR (TH). CD4 binds MHC-II β2 domain.
2. Costimulatory: CD28 (TH) + B7 (APC).
3. Cytokine: IL-1 (macrophage) → TH.

Transduction: CD4 → CD3 complex.

Activated TH → secretes IL-2 + IL-2R (CD25) → autocrine/paracrine proliferation → lymphoblast → Effector TH (short-lived) / Memory TH (long-lived, CD45RO vs naive CD45RA).

TH1: IL-2, IFN-γ, TNF-β → activates TC cells, CMI. IL-12 (macrophage) promotes TH1. TH2: IL-4, IL-5, IL-6, IL-10, IL-13 → activates B cells, AMI (antibody production).

CMI

Role: ONLY defense for obligate intracellular organisms (all viruses, Mycobacterium/Chlamydia/Rickettsia, Plasmodium/Leishmania/Trypanosoma/Cryptosporidium, Pneumocystis). Facultative intracellular (Listeria, Salmonella, Yersinia, Histoplasma, Cryptococcus): humoral extracellular phase, CMI once intracellular. Also: tumor immunity, Type IV hypersensitivity, transplant rejection, GVH reaction.

CTL (Cytotoxic T Lymphocyte, CD8+)

Naive TC responds to viral/tumor peptide (cytosolic pathway, MHC-I). Activation signals: TCR-CD3+MHC-I-peptide (CD8-α3 domain) / CD28-B7 / IL-2 (from TH1) on IL-2R. Kill via Perforins (pore formation) + Granzymes (serine protease → apoptosis via caspase).

NK Cells

10-15% peripheral blood lymphocytes. Separate lineage. Innate immunity — antigen-nonspecific, no prior exposure needed, NO memory. Markers: CD16, CD56 (NOT CD3/CD4/CD8 — “null cells”). No MHC restriction.

Opposing-signals model:

• Activation receptors (NKR-P1, CD16) — bind ligand → activate
• Inhibitory receptors — bind MHC-I (HLA-E) on normal cells → suppress (DOMINANT signal)
• Virus-infected/tumor cells: ↓MHC-I → no inhibitory signal → activation wins → killing

Mechanism: perforins + granzymes (SAME as TC, but CONSTITUTIVE not inducible). Also: responds to IL-12 (macrophage) → secretes IFN-γ → activates macrophages. + ADCC.

ADCC

Nonspecific cytotoxic cells (NK, macrophage, monocyte, neutrophil, eosinophil) have Fc receptors → bind Fc of antibody on target cell → lysis. Antibody specificity directs nonspecific cell. NO complement involved.

Releases: perforins/granzymes (NK), lytic enzymes (neutrophil), lytic enzymes+perforins (eosinophil — anti-helminthic), lytic enzymes+TNF (macrophage).

Detection of CMI: MLR (mixed lymphocyte reaction — T cell proliferation), CML (cell-mediated lympholysis — cytotoxic function), GVH reaction (in vivo, animal).

AMI (Humoral)

3 steps: B cell activation → proliferation/differentiation (plasma+memory cells) → effector function (neutralization, opsonization, complement activation).

B Cell Activation

TD (thymus-dependent) antigens — most antigens — need T cell help (via APC→TH→cytokine→B cell). TI (thymus-independent) antigens (e.g. bacterial capsule) — direct B cell activation, no T cell help.

TD pathway: B cell mIg recognizes antigen → receptor-mediated endocytosis → process → present with MHC-II to activated TH.

3 signals:

1. Membrane IgM cross-linking by antigen
2. CD40 (B cell) + CD40L (activated TH)
3. Cytokine (TH) → cytokine receptor (B cell)

BCR = membrane Ig (antigen-binding) + Ig-α/Ig-β heterodimer (transduction).

Germinal Center Reaction

Naive B cells → B-cell zones (lymph node cortex, splenic marginal zone) → primary follicles → (antigen exposure) → secondary follicles with germinal center (dark zone + light zone).

Dark zone: activated B cell → centroblast (large, dividing) → centrocyte (small, non-dividing). Somatic hypermutation: random point mutations in Ig variable region → alters affinity (high or low, random). Low affinity centrocyte → apoptosis → cleared by tingible body macrophages. High affinity centrocyte → survives → migrates to light zone. = AFFINITY MATURATION.

Light zone: centrocytes bind Follicular Dendritic Cells (FDC). FDC ≠ APC. No MHC-II. Has Fc receptors → holds Ag-Ab complex long-term → lets centrocytes compete/select by affinity. Selected centrocytes → Class switchover (interact with activated TH + cytokine signal):

• IFN-γ → IgG2a/IgG3
• IL-5+TGF-β → IgA/IgG2b
• IL-4 → IgE/IgG1/IgG4 IgM = predominant early; class switch generates other classes as response matures.

Differentiation: Plasma cells (large, antibody-secreting, NO membrane Ig, no further switching) + Memory cells (long-lived, HIGH affinity membrane Ig of ALL classes vs naive B cell’s low-affinity IgM/IgD only).

Effector Functions of AMI (via Fc portion)

• Opsonization: Fc receptor (phagocyte) + antibody-coated microbe → ↑phagocytosis
• Transcytosis: poly-Ig receptor (basolateral epithelial surface) binds IgA dimer/IgM multimer → shuttled to apical/lumen surface. = basis of mucosal immunity (IgA neutralizes at mucosa)
• Complement activation: Ag-Ab complex → classical pathway → MAC (C5-C9) → lysis
• ADCC: as above, antibody directs nonspecific killer cells

Two Arms, One Coordinated System

Acquired immunity plays out through two distinct but interlinked responses. Cell-mediated immunity (CMI) destroys cells that harbour intracellular microbes or that have become abnormal — tumour cells being the other major target — using specific and nonspecific effector cells, chiefly the cytotoxic T cell. Antibody-mediated (humoral) immunity (AMI) protects against microbes on cell surfaces and in extracellular fluid by secreting antibodies, but has essentially no reach against anything already inside a host cell. The helper T cell sits at the centre of both, since its activation and differentiation is what regulates the downstream behaviour of each arm.

Helper T Cell Activation

Three signals are required to activate a naive helper T cell (TH), and losing sight of any one of them is a common source of confusion when working through the antigen-presentation pathway:

1. Antigen-specific signal — the antigenic peptide sitting in the groove of MHC-II on an antigen-presenting cell (APC) binds the T cell receptor (TCR) on the TH cell surface, with the TH cell’s CD4 molecule additionally engaging the β2 domain of MHC-II.
2. Costimulatory signal — CD28 on the TH cell binds B7 on the APC.
3. Cytokine signal — APCs (chiefly macrophages) secrete IL-1, which acts on the TH cell.

Signal transduction runs through the CD4 molecule interacting with the CD3 complex, which relays the activating signal onward. Activated TH cells then secrete IL-2 and its own receptor (IL-2R/CD25); IL-2 acts back on the same cell and on neighbouring TH cells, driving naive TH cells to proliferate and differentiate into lymphoblasts, which go on to become either short-lived effector TH cells or long-lived memory TH cells (identifiable by their CD45RO isoform, versus CD45RA on naive cells).

Effector TH cells split into two functionally distinct subsets, and which subset dominates decides whether the response tilts cellular or humoral: TH1 cells secrete IL-2, IFN-γ, and TNF-β, driving cytotoxic T cell activation and cell-mediated immunity; TH2 cells secrete IL-4, IL-5, IL-6, IL-10, and IL-13, driving B cells toward antibody production. IL-12 from macrophages tips this balance toward TH1.

Cell-Mediated Immune Response

Role of CMI

CMI is the only effective defence against obligate intracellular organisms — every virus, several bacteria (Mycobacterium, Chlamydia, Rickettsia), several parasites (Plasmodium, Leishmania, Trypanosoma, Cryptosporidium), and Pneumocystis among fungi — since humoral immunity simply cannot reach inside a cell. For facultative intracellular organisms (Listeria, Salmonella, Yersinia, Histoplasma, Cryptococcus), humoral immunity handles the extracellular phase, and CMI takes over once the organism moves inside a cell. CMI also clears tumour and other abnormal cells, mediates type IV (delayed) hypersensitivity, and drives transplant rejection and graft-versus-host reactions.

Cytotoxic T Lymphocytes (CTL)

CD8+ cytotoxic T cells (TC) are the principal antigen-specific effector of CMI. Naive TC cells respond to viral or tumour peptides processed via the cytosolic pathway and presented with MHC class I. Activation again requires three signals: TCR-CD3 binding MHC-I-peptide (with CD8 engaging the α3 domain of MHC-I), CD28 binding B7 on the target cell, and IL-2 (from TH1 cells) acting on the high-affinity IL-2 receptor.

Activated TC cells kill via two enzymes: perforins punch pores in the target membrane, through which granzymes — serine proteases — enter and trigger apoptosis via the caspase pathway.

Natural Killer (NK) Cells

NK cells are large granular lymphocytes, 10–15% of peripheral blood lymphocytes, from a distinct lymphoid lineage. Unlike TC cells they are part of innate immunity — antigen-nonspecific, no prior sensitization needed, no memory formed — and act as a stopgap against virus-infected and tumour cells until TC cells activate and take over.

NK cells lack the T cell markers CD3/CD4/CD8 (hence “null cells”) and instead carry CD16 and CD56. Their killing decision follows an opposing-signals model: activation receptors (NKR-P1, CD16) trigger killing when bound to a target-cell ligand, but inhibitory receptors recognizing MHC-I (HLA-E) on any normal cell generate a dominant suppressive signal that overrides activation. Virus-infected and tumour cells characteristically downregulate MHC-I, removing the inhibitory brake and leaving the activation signal unopposed — the mechanism by which NK cells selectively find altered cells. Target lysis then proceeds by the same perforin/granzyme mechanism as TC cells, except NK cells express these enzymes constitutively (always cytotoxic-ready) rather than only after antigen exposure. NK cells also respond to macrophage-derived IL-12 by secreting IFN-γ, which activates macrophages in turn, and participate in ADCC (below).

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

Various nonspecific cytotoxic cells (NK cells, macrophages, monocytes, neutrophils, eosinophils) express Fc receptors that bind the Fc portion of antibody already coated on a target cell. The antibody’s specificity directs an otherwise nonspecific killer cell to the right target, which then releases perforins, granzymes, lytic enzymes, free radicals, and TNF — but no complement is involved. Eosinophil-mediated ADCC (IgE-directed) is central to anti-helminthic immunity; NK-cell-mediated ADCC (IgG-directed) matters for tumour cells and virus-infected cells.

CMI can be assessed in the lab by the mixed-lymphocyte reaction (MLR, tests T cell proliferation), cell-mediated lympholysis (CML, tests cytotoxic function), or the graft-versus-host reaction in animal models.

Antibody-Mediated (Humoral) Immune Response

AMI runs through three sequential steps: B cell activation on contact with antigen, proliferation/differentiation into plasma cells and memory cells, and finally antibody-mediated effector function (neutralization, opsonization, complement activation).

B Cell Activation

Antigens activate B cells by one of two routes. Thymus-dependent (TD) antigens — most antigens — need T cell help: an APC processes and presents the antigen to a TH cell, whose cytokines then activate the B cell. Thymus-independent (TI) antigens (e.g. bacterial capsular polysaccharide) skip APC processing and activate B cells directly, without T cell cytokine help.

For TD antigens, the B cell itself first acts as an APC — its membrane immunoglobulin (mIg) recognizes the antigen, internalizes it by receptor-mediated endocytosis, and presents processed peptide with MHC-II to an already-activated TH cell. Three signals then activate the B cell: Signal 1 is cross-linking of membrane IgM by the antigen itself; Signal 2 is CD40 on the B cell binding CD40L on the activated TH cell; Signal 3 is a cytokine from the TH cell binding its receptor on the B cell. Signal transduction runs through the B cell receptor (BCR) — antigen-binding membrane Ig plus an Ig-α/Ig-β heterodimer that relays the signal once the membrane Ig is cross-linked.

Germinal Centre Reaction

Naive B cells settle in B-cell zones of peripheral lymphoid organs (lymph node cortex, splenic marginal zone) as primary lymphoid follicles. After antigenic exposure, these transform into secondary follicles bearing a germinal centre with two zones:

Dark zone — activated B cells become large, dividing centroblasts, which shrink into non-dividing centrocytes while undergoing somatic hypermutation: random point mutations in the Ig variable-region gene that alter membrane-Ig antigen-binding affinity. Because the mutations are random, they produce both higher- and lower-affinity variants. Low-affinity centrocytes die by apoptosis and are cleared by tingible body macrophages; high-affinity centrocytes survive and migrate to the light zone — the process of affinity maturation.

Light zone — surviving centrocytes bind follicular dendritic cells (FDCs), a specialized dendritic-cell type that does not process antigen or express MHC-II, but instead holds antigen-antibody complexes on its Fc receptors for prolonged periods via Fc receptors, letting centrocytes compete for binding and be selected on affinity. Selected centrocytes then undergo class switchover — interacting with activated TH cells and receiving a cytokine signal that switches which Ig class they’ll secrete (IFN-γ → IgG2a/IgG3; IL-5+TGF-β → IgA/IgG2b; IL-4 → IgE/IgG1/IgG4). Early in any response IgM predominates; class switchover is what generates the other classes as the response matures. Finally, class-switched centrocytes differentiate into plasma cells (large, antibody-secreting, no membrane Ig, no further switching) and memory cells (long-lived, high-affinity membrane Ig of all classes, ready for rapid response on re-exposure — unlike naive B cells, which carry only low-affinity IgM/IgD).

Effector Functions of AMI

Secreted antibody works through its Fc portion binding Fc receptors on various cells:

• Opsonization — Fc receptors on phagocytes recognize antibody-coated microbes, enhancing phagocytosis.
• Transcytosis — poly-Ig receptors on the basolateral surface of epithelial cells bind IgA dimers and IgM multimers and shuttle them to the apical surface into a lumen (e.g. gut) — the basis of mucosal immunity, since transcytosed IgA neutralizes microbes right at the mucosal surface.
• Complement activation — antigen-antibody complexes trigger the classical pathway, ending in the membrane attack complex (C5-C9), which lyses the target.
• ADCC — as described above, antibody specificity directs nonspecific cytotoxic cells to their target.

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