12.2 Adaptive Immunity: T-Cell & B-Cell Activation, MHC Restriction, and Antibodies

12.2 Adaptive Immunity: T-Cell & B-Cell Activation, MHC Restriction, and Antibodies

Adaptive immunity provides antigen-specific protection characterized by clonal expansion of antigen-reactive lymphocytes and the generation of immunological memory. The major executioners of adaptive immunity are T lymphocytes (cell-mediated immunity) and B lymphocytes (humoral immunity).

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Major Histocompatibility Complex (MHC) Architecture

The Major Histocompatibility Complex (MHC), known in humans as the Human Leukocyte Antigen (HLA) complex, encodes cell-surface glycoproteins that present peptide fragments to T-cell receptors (TCRs).

   +------------------------+-----------------------------------+-----------------------------------+
   | Feature                | MHC Class I                       | MHC Class II                      |
   +------------------------+-----------------------------------+-----------------------------------+
   | HLA Genes              | HLA-A, HLA-B, HLA-C               | HLA-DP, HLA-DQ, HLA-DR            |
   | Cellular Distribution  | All nucleated cells (absent RBCs) | Professional APCs (Dendritic,     |
   |                        |                                   | Macrophages, B cells)             |
   | Molecular Structure    | Alpha chain (a1, a2, a3) +        | Alpha chain (a1, a2) +            |
   |                        | beta-2 microglobulin              | Beta chain (b1, b2)               |
   | Antigen Source         | Intracellular / Endogenous        | Extracellular / Exogenous         |
   |                        | (viral, mutated tumor proteins)   | (phagocytosed bacteria, toxins)   |
   | Processing Machinery   | Proteasome, TAP transporter       | Endolysosome, Invariant chain,    |
   |                        |                                   | CLIP, HLA-DM                      |
   | Responding Lymphocyte  | CD8+ Cytotoxic T cells            | CD4+ Helper T cells               |
   | T-Cell Co-receptor Site| CD8 binds a3 domain               | CD4 binds b2 domain               |
   +------------------------+-----------------------------------+-----------------------------------+

MHC Class I Pathway (Endogenous Antigen Presentation)

1. Intracellular proteins (e.g., viral proteins synthesized in the cytosol or mutated self-proteins) are ubiquitinated and degraded by the proteasome.
2. Peptides are transported into the lumen of the endoplasmic reticulum (ER) via the TAP (Transporter associated with Antigen Processing) protein complex.
3. Peptides are loaded into the peptide-binding groove of newly synthesized MHC Class I heavy chains complexed with $\beta_2$-microglobulin.
4. The MHC I-peptide complex is transported to the plasma membrane and presented to CD8+ Cytotoxic T Lymphocytes (CTLs).

MHC Class II Pathway (Exogenous Antigen Presentation)

1. Extracellular pathogens or proteins are internalized by endocytosis or phagocytosis into endosomes/lysosomes and degraded into peptide fragments by acid proteases.
2. In the ER, newly synthesized MHC Class II $\alpha\beta$ heterodimers bind the Invariant Chain ($I_i$), which blocks premature peptide binding in the ER and directs the MHC Class II molecule into late endosomal compartments.
3. Within the endosome, the invariant chain is cleaved, leaving a small fragment called CLIP (Class II-associated invariant chain peptide) in the binding groove.
4. HLA-DM catalyzes the removal of CLIP, allowing exogenous antigenic peptides to bind the MHC Class II groove.
5. The MHC Class II-peptide complex travels to the cell surface for presentation to CD4+ Helper T cells.

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T-Cell Development and Differentiation

T-cell progenitor cells migrate from the bone marrow to the thymus, where they undergo TCR gene rearrangement and stringent selection processes.

Thymic Selection (Central Tolerance)

• Positive Selection (Thymic Cortex): Double-positive ($CD4^+CD8^+$) immature thymocytes interact with cortical thymic epithelial cells presenting self-peptides on MHC Class I and Class II. Thymocytes whose TCR recognizes self-MHC with moderate affinity receive survival signals (MHC restriction). Thymocytes that bind MHC Class I downregulate CD4 to become $CD8^+$ single-positive cells; those that bind MHC Class II downregulate CD8 to become $CD4^+$ single-positive cells. Cells unable to bind self-MHC undergo apoptosis ("death by neglect").
• Negative Selection (Thymic Medulla): Single-positive thymocytes encounter medullary thymic epithelial cells (mTECs) and dendritic cells. mTECs express the AIRE (Autoimmune Regulator) gene, which drives ectopic transcription of tissue-restricted self-antigens (e.g., insulin, thyroid proteins). Thymocytes displaying high-affinity binding to self-MHC/self-antigen complexes undergo apoptotic deletion or convert into regulatory T cells. Mutations in AIRE cause APECED / APS-1 (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy).

CD4+ T Helper Subsets

Upon encountering antigen on APCs, naive CD4+ T helper ($Th0$) cells differentiate into specialized effector subsets dictated by the local cytokine environment:

                  +---> Th1  (IL-12, IFN-g)  --> IFN-g, IL-2  [Macrophage activation, Intracellular pathogens]
                  |
                  +---> Th2  (IL-4)          --> IL-4, 5, 13  [Helminths, Allergy, IgE class switch]
Naive CD4+ T cell --|
                  +---> Th17 (IL-6, TGF-b)   --> IL-17, IL-22 [Extracellular bacteria/fungi, Neutrophils]
                  |
                  +---> Treg (TGF-b)         --> IL-10, TGF-b [Immune suppression, Peripheral tolerance]

• Th1 Subsets: Induced by IL-12 and IFN-$\gamma$ (transcription factor T-bet). Secretes IFN-$\gamma$ and IL-2. IFN-$\gamma$ activates macrophages (enhancing phagolysosomal killing), promotes IgG2a/IgG3 opsonizing antibody production, and mediates cell-mediated immunity against intracellular pathogens (Mycobacterium tuberculosis, Leishmania).
• Th2 Subsets: Induced by IL-4 (transcription factor GATA-3). Secretes IL-4, IL-5, and IL-13. IL-4 and IL-13 drive B-cell class switching to IgE; IL-5 stimulates eosinophil growth and activation. Mediates defense against helminthic parasites and drives Type I hypersensitivity (allergic) reactions.
• Th17 Subsets: Induced by IL-6, TGF-$\beta$, and IL-23 (transcription factor ROR$\gamma t$). Secretes IL-17 and IL-22. IL-17 recruits neutrophils to clear extracellular bacterial and fungal infections (Candida albicans). Mutations in STAT3 impair Th17 generation, causing Hyper-IgE Syndrome (Job Syndrome) (cold staph abscesses, eczema, retained primary teeth).
• Treg Subsets: Phenotype $CD4^+CD25^+\text{FOXP3}^+$ (transcription factor FOXP3). Secretes anti-inflammatory cytokines IL-10 and TGF-$\beta$. Maintains peripheral self-tolerance and suppresses autoreactive T-cell responses. Mutations in FOXP3 lead to IPEX Syndrome (Immunodysregulation Polyendocrinopathy Enteropathy X-linked).

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B-Cell Activation and Antibody Isotypes

B cells develop in the bone marrow, where immunoglobulin heavy and light chain genes undergo somatic rearrangement.

Somatic Recombination and B-Cell Activation

• V(D)J Recombination: In the bone marrow, RAG-1 and RAG-2 (Recombination Activating Genes) randomly recombine Variable (V), Diversity (D), and Joining (J) gene segments for the heavy chain, and V and J segments for the light chain ($\kappa$ or $\lambda$). Terminal deoxynucleotidyl transferase (TdT) inserts non-templated nucleotides at gene junctions, maximizing antigen receptor diversity.
• T-Cell-Dependent B-Cell Activation: Mature naive B cells internalize antigen via surface IgM/IgD, processing and presenting peptides on MHC Class II to activated CD4+ T follicular helper ($T_{FH}$) cells. Interaction requires two signals:
  1. TCR binding to MHC II-peptide complex.
  2. CD40L (CD154) on T cell binding to CD40 on B cell.
• Class Switch Recombination (CSR) & Somatic Hypermutation (SHM): T-cell-derived cytokines (IL-4, IFN-$\gamma$, TGF-$\beta$) and CD40 ligation induce the enzyme Activation-Induced Cytidine Deaminase (AID) in lymph node germinal centers. AID mediates class switching of the heavy chain constant region from $C_\mu$ to $C_\gamma, C_\alpha, \text{or } C_\epsilon$, and introduces point mutations in variable regions (somatic hypermutation) to select high-affinity antibodies (affinity maturation). Defects in CD40L cause Hyper-IgM Syndrome.

Immunoglobulin Structure and Isotypes

Antibodies consist of two identical heavy (H) chains and two identical light (L) chains connected by disulfide bonds. The Fab region (variable domain) binds antigen; the Fc region (constant domain) dictates biological isotype function (complement fixation, Fc receptor binding).

   Fab Region (Antigen Binding)
      \       /
       \     /
        +---+  <-- Disulfide Hinge
        |   |
        |   |
   Fc Region (Complement Fixation & Fc Receptor Binding)

• IgG: Monomer. Most abundant serum immunoglobulin (~75–80%). Longest serum half-life (~21 days). Only antibody class that crosses the placenta, conferring passive immunity to the fetus. Predominates in secondary (anamnestic) immune responses. Acts as a major opsonin and activates classical complement.
• IgA: Monomer in serum; dimer joined by a J-chain in mucosal secretions (tears, saliva, colostrum, GI and respiratory mucus). Acquires a Secretory Component from the polymeric Ig receptor (pIgR) during transepithelial transport, resisting enzymatic degradation in mucosal lumens. Inhibits microbial adherence to mucosal surfaces.
• IgM: Monomer on naive B-cell surfaces; pentamer joined by a J-chain when secreted. Produced first during primary immune responses. Possesses 10 antigen-binding sites, conferring highest avidity (overall binding strength). Most potent activator of the classical complement pathway.
• IgE: Monomer. Maintains extremely low serum concentrations. Binds high-affinity $Fc\epsilon RI$ receptors on mast cells and basophils. Cross-linking of surface IgE by allergen induces immediate degranulation (histamine, leukotrienes), driving Type I hypersensitivity. Mediates eosinophil-dependent ADCC against helminths.
• IgD: Monomer. Co-expressed with IgM on the surface of mature naive B cells via alternative RNA splicing. Functions as an antigen receptor involved in B-cell maturation.