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14.8 Adaptive Cellular Immunity: T Cells, Thymic Selection & MHC Presentation
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14.8 Adaptive Cellular Immunity: T Cells, Thymic Selection & MHC Presentation
Key Takeaways Explain This Topic AI
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 α \alpha α heavy chain ( α 1 , α 2 , α 3 \alpha_1, \alpha_2, \alpha_3 α 1 , α 2 , α 3 ) non-covalently paired with invariant β 2 -microglobulin \boldsymbol{\beta_2\text{-microglobulin}} β 2 -microglobulin Heterodimer of polymorphic α \boldsymbol{\alpha} α chain ( α 1 , α 2 \alpha_1, \alpha_2 α 1 , α 2 ) and polymorphic β \boldsymbol{\beta} β chain ( β 1 , β 2 \beta_1, \beta_2 β 1 , β 2 )
Peptide Binding Groove Closed at both ends; binds short peptides ( 8–10 amino acids ) formed by α 1 \alpha_1 α 1 and α 2 \alpha_2 α 2 domains Open at both ends; accommodates longer, variable peptides ( 13–25 amino acids ) formed by α 1 \alpha_1 α 1 and β 1 \beta_1 β 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 CD8 + \text{CD8}^+ CD8 + Cytotoxic T Lymphocytes (CTLs) CD4 + \text{CD4}^+ CD4 + Helper T Lymphocytes ( T h T_h T h )
T-Cell Subsets and Effector Functions
CD4 + \text{CD4}^+ CD4 + Helper T Cells ( T h T_h T h ) : Activated by professional APCs displaying peptide-MHC II complexes. Upon activation, they differentiate into specialized effector lineages guided by polarizing cytokines:
T h 1 T_h1 T h 1 : Induced by IL-12 (from dendritic cells) and IFN- γ \gamma γ ; express transcription factor T-bet . Secrete IFN- γ \gamma γ 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 h 2 T_h2 T h 2 : 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 h 17 T_h17 T h 17 : Induced by TGF- β \beta β , IL-6, and IL-23; express ROR γ \gamma γ t . Secrete IL-17 and IL-22 , recruiting neutrophils to eliminate extracellular bacteria and fungi at mucosal barriers.
T r e g T_{reg} T re g (Regulatory T Cells) : Phenotypically CD4 + CD25 + FoxP3 + \text{CD4}^+\text{CD25}^+\text{FoxP3}^+ CD4 + CD25 + 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- β \beta β .
CD8 + \text{CD8}^+ 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:
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.
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).