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14.8 Adaptive Cellular Immunity: T Cells, Thymic Selection & MHC Presentation

Key Takeaways

Cellular adaptive immunity requires rigorous thymic education where double-positive thymocytes undergo positive selection in the cortex for MHC self-restriction and negative selection in the medulla via AIRE to delete high-avidity self-reactive clones, establishing central tolerance.
MHC Class I molecules (expressed on all nucleated cells) present endogenous proteasome-derived peptides to CD8+ cytotoxic T lymphocytes (8 x 1 = 8), whereas MHC Class II molecules (expressed on professional APCs) present exogenous endolysosomal peptides to CD4+ helper T lymphocytes (4 x 2 = 8).
Lymph nodes, spleen, and mucosa-associated lymphoid tissue are the secondary lymphoid organs where naive lymphocytes meet antigen: dendritic cells migrate there carrying antigen, T and B cells occupy distinct paracortical and follicular zones, and germinal centres within the follicles are the site of somatic hypermutation and affinity maturation.

Last updated: September 2026

14.8 Adaptive Cellular Immunity: T Cells, Thymic Selection & MHC Presentation

Adaptive Cellular Immunity: T Cells, Thymic Selection & MHC Presentation

T lymphocyte progenitors originate in the bone marrow and migrate via the bloodstream to the thymus for maturation and education:

Thymic Education of T Cells:
1. Double-Negative (DN: CD4- CD8-): Progenitor thymocytes arrive in the thymic cortex; rearrange TCR beta chain.
2. Double-Positive (DP: CD4+ CD8+): Express fully rearranged alpha-beta TCR along with both CD4 and CD8 coreceptors.
3. Positive Selection (Thymic Cortex):
   Cortical Thymic Epithelial Cells (cTECs) display self-peptides on MHC Class I and Class II.
   Thymocytes whose TCR binds self-MHC with low-to-moderate affinity receive survival signals (MHC Restriction).
   Those unable to recognize self-MHC die by apoptosis ('death by neglect', ~95% of thymocytes).
   Determines coreceptor lineage: cells recognizing MHC I downregulate CD4 to become CD8+; cells recognizing MHC II downregulate CD8 to become CD4+.
4. Negative Selection (Thymic Medulla):
   Medullary Thymic Epithelial Cells (mTECs) and dendritic cells display self-antigens.
   mTECs express the Autoimmune Regulator (AIRE) transcription factor, driving promiscuous expression of tissue-restricted
   peripheral self-antigens (insulin, thyroglobulin, myelin).
   Thymocytes that bind self-antigen/MHC with abnormally high avidity are deleted via apoptosis (Clonal Deletion).
   Failure of AIRE causes Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED).

MHC Class I vs. MHC Class II Pathways

The Rule of Eights (Coreceptor Binding Specificity):
- CD8 binds MHC Class I  -->  8 x 1 = 8
- CD4 binds MHC Class II -->  4 x 2 = 8

Feature	MHC Class I	MHC Class II
Polypeptide Composition	Polymorphic $\alpha$ heavy chain ( $\alpha_1, \alpha_2, \alpha_3$ ) non-covalently paired with invariant $\boldsymbol{\beta_2\text{-microglobulin}}$	Heterodimer of polymorphic $\boldsymbol{\alpha}$ chain ( $\alpha_1, \alpha_2$ ) and polymorphic $\boldsymbol{\beta}$ chain ( $\beta_1, \beta_2$ )
Peptide Binding Groove	Closed at both ends; binds short peptides (8–10 amino acids) formed by $\alpha_1$ and $\alpha_2$ domains	Open at both ends; accommodates longer, variable peptides (13–25 amino acids) formed by $\alpha_1$ and $\beta_1$ domains
Cellular Distribution	All nucleated somatic cells and platelets (absent on mature non-nucleated erythrocytes)	Professional APCs only: Dendritic cells, Macrophages, B lymphocytes (and thymic epithelium)
Antigen Source	Endogenous (Intracellular): Viral proteins, mutated tumor proteins, cytosolic self-proteins	Exogenous (Extracellular): Engulfed bacteria, extracellular toxins, fungal antigens
Antigen Processing Machinery	Cytosolic Proteasome degrades ubiquitinated proteins $\to$ peptides transported into ER via TAP1/TAP2 heterodimer	Antigens internalized by endocytosis/phagocytosis $\to$ degraded in acidified Endolysosomes by cathepsins
Chaperones & Assembly	Assembled in ER with calnexin, calreticulin, and tapasin; peptide loading occurs in the ER lumen	Assembled in ER with Invariant Chain (Ii) blocking the groove $\to$ Ii cleaved to CLIP in endolysosome $\to$ HLA-DM catalyzes CLIP displacement by antigenic peptide
Recognizing T Cell Subset	$\text{CD8}^+$ Cytotoxic T Lymphocytes (CTLs)	$\text{CD4}^+$ Helper T Lymphocytes ( $T_h$ )

T-Cell Subsets and Effector Functions

$\text{CD4}^+$ Helper T Cells ( $T_h$ ): Activated by professional APCs displaying peptide-MHC II complexes. Upon activation, they differentiate into specialized effector lineages guided by polarizing cytokines:
- $T_h1$ : Induced by IL-12 (from dendritic cells) and IFN- $\gamma$ ; express transcription factor T-bet. Secrete IFN- $\gamma$ and IL-2. Activate macrophages (enhancing phagolysosomal fusion and nitric oxide production), stimulate CTL proliferation, and drive cell-mediated clearance of intracellular pathogens (Mycobacterium tuberculosis, Listeria, viruses).
- $T_h2$ : Induced by IL-4; express transcription factor GATA-3. Secrete IL-4 (drives B-cell class switching to IgE), IL-5 (activates eosinophils), and IL-13 (mucus secretion and peristalsis). Direct host defense against extracellular parasitic helminths and drive allergic asthma.
- $T_h17$ : Induced by TGF- $\beta$ , IL-6, and IL-23; express ROR $\gamma$ t. Secrete IL-17 and IL-22, recruiting neutrophils to eliminate extracellular bacteria and fungi at mucosal barriers.
- $T_{reg}$ (Regulatory T Cells): Phenotypically $\text{CD4}^+\text{CD25}^+\text{FoxP3}^+$ . Suppress autoreactive T-cell responses and limit tissue inflammation via cell-cell contact (CTLA-4) and secretion of immunosuppressive cytokines: IL-10 and TGF- $\beta$ .
$\text{CD8}^+$ Cytotoxic T Lymphocytes (CTLs): Activated when their TCR engages an endogenous peptide-MHC I complex on an infected target cell. CTLs deliver targeted, antigen-specific cell death through two redundant pathways:
1. Perforin/Granzyme Pathway: Directional exocytosis of cytotoxic granules into the immunological synapse. Perforin inserts into the target membrane, forming a pore that allows Granzyme B to enter. Granzyme B directly cleaves and activates procaspase-3 and cleaves BID into truncated BID (tBID), which translocates to mitochondria, triggering cytochrome c release, apoptosome assembly, and rapid apoptotic cell death.
2. Fas/FasL Pathway: Activated CTLs express surface Fas Ligand (FasL / CD178), which cross-links Fas (CD95) death receptors on the target cell surface, recruiting FADD and procaspase-8 to form the Death-Inducing Signaling Complex (DISC), activating executioner caspases.

Lymphatic System and Secondary Lymphoid Organs

Secondary Lymphoid Organs: Microarchitectural Organization
- Lymph Nodes: Encapsulated organs filtering lymph draining from peripheral tissues.
  - Cortex: B-cell zone containing primary follicles and secondary Germinal Centers.
  - Paracortex: T-cell zone containing High Endothelial Venules (HEVs) through which circulating lymphocytes extravasate; undergoes massive hyperplasia during cellular immune responses.
  - Medulla: Contains Medullary Cords (rich in plasma cells secreting antibodies) and Medullary Sinuses (lined by reticular fibers and macrophages filtering lymph).
- Spleen: Largest secondary lymphoid organ; lacks afferent lymphatics; filters systemic blood.
  - Red Pulp: Venous sinusoids and splenic cords (of Billroth) lined by macrophages; destroys senescent RBCs and removes unopsonized blood-borne bacteria.
  - White Pulp: Immunological zone; Periarteriolar Lymphoid Sheaths (PALS, predominantly T cells surrounding central arterioles) and lymphoid follicles (predominantly B cells).
  * Asplenic individuals (surgical removal or sickle cell autoinfarction) face overwhelming sepsis from encapsulated bacteria (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae).

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Dual Antigen Presentation Pathways: Endogenous MHC Class I vs Exogenous MHC Class II

Test Your Knowledge

A researcher discovers a novel human genetic mutation that results in complete loss of function of the Transporter associated with Antigen Processing (TAP1/TAP2) complex. Which immunological defect will be observed in a patient homozygous for this mutation?

Failure to clear extracellular encapsulated bacterial infections due to an inability of B cells to present antigen on surface MHC Class II molecules.

Impaired activation of CD4+ helper T cells caused by defective endolysosomal degradation of engulfed viral capsid proteins.

Severe susceptibility to intracellular viral infections due to an inability to translocate cytosolic proteasomal peptides into the endoplasmic reticulum, abolishing surface MHC Class I presentation to CD8+ cytotoxic T cells.

Complete absence of natural killer (NK) cell cytotoxic activity due to over-expression of inhibitory killer-cell immunoglobulin-like receptors.

Test Your Knowledge

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) is a rare hereditary disorder caused by loss-of-function mutations in the Autoimmune Regulator (AIRE) gene. How does the failure of AIRE function lead to widespread multiorgan autoimmune destruction?

Medullary thymic epithelial cells fail to ectopically express tissue-restricted self-antigens, preventing negative selection and allowing high-avidity autoreactive CD4+ and CD8+ T cells to escape into the peripheral circulation.

Cortical thymic epithelial cells fail to express MHC Class II molecules, leading to the apoptotic death of all developing regulatory T (Treg) cells during positive selection.

Dendritic cells in peripheral lymph nodes overproduce interleukin-12, driving excessive differentiation of naive T cells into pathogenic Th17 inflammatory subsets.

Splenic red pulp macrophages fail to phagocytose apoptotic thymocytes, triggering the accumulation of extracellular nucleic acids and hyperactivation of complement C3.

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