T cell Study Guide

📖 Core Concepts T‑cell receptor (TCR) – membrane protein (α + β chains) that recognizes peptide‑MHC complexes; generated by random V‑D‑J recombination. Positive selection – thymocytes that weakly bind self‑MHC receive survival signals → become CD4⁺ (MHC II) or CD8⁺ (MHC I) T cells. Negative selection – thymocytes that bind self‑antigen too strongly are deleted (central tolerance) or become regulatory T cells (Tregs). Two‑signal activation – Signal 1: TCR + peptide‑MHC. Signal 2: CD28 + B7 (CD80/86). Lack of Signal 2 → anergy. T‑cell exhaustion – progressive loss of effector function after chronic antigen exposure; marked by high PD‑1, TIM‑3, LAG‑3, CTLA‑4. Checkpoint blockade – therapeutic antibodies that block inhibitory receptors, restoring T‑cell activity. --- 📌 Must Remember CD4⁺ vs CD8⁺: CD4⁺ → MHC II → helper functions; CD8⁺ → MHC I → cytotoxic killing. Selection checkpoints: β‑selection (DN3): successful TCR‑β + pre‑Tα → stop further β rearrangement. Positive selection → CD4⁺ or CD8⁺ lineage. Negative selection → apoptosis or Treg diversion. Key activation markers: CD69 (early), CD25 (IL‑2Rα), CD71 (transferrin receptor). Exhaustion signature: ↑ PD‑1, TIM‑3, LAG‑3, CTLA‑4; ↓ IL‑2, TNF‑α, IFN‑γ. Checkpoint inhibitors: anti‑PD‑1 (pembrolizumab, nivolumab), anti‑CTLA‑4 (ipilimumab). Memory subsets: Central memory (CCR7⁺, CD62L⁺). Effector memory (CCR7⁻, CD62L⁻). Tissue‑resident (CD103⁺). --- 🔄 Key Processes Thymic Development HSC → multipotent progenitor → common lymphoid progenitor (CLP) → migrate to thymus → thymocyte. DN (CD4⁻CD8⁻) → β‑selection (RAG‑mediated V‑D‑J recombination). DP (CD4⁺CD8⁺) → positive selection (MHC binding) → single‑positive CD4⁺ or CD8⁺. Negative selection in medulla (mTECs presenting tissue‑specific antigens). T‑cell Activation (CD4⁺) Signal 1: TCR‑pMHC II binding. Signal 2: CD28‑B7 interaction → PI3K → PIP₃. ITAM phosphorylation → ZAP‑70 → LAT scaffold → PLC‑γ activation. PLC‑γ hydrolyzes PIP₂ → DAG + IP₃ → Ca²⁺ release → calcineurin → NFAT dephosphorylation. NFAT + NF‑κB + AP‑1 → transcription of IL‑2 and other genes. Exhaustion Induction Persistent TCR signaling + inadequate co‑stimulation → up‑regulation of inhibitory receptors + IL‑10/TGF‑β signaling → functional decline. Checkpoint Blockade Therapy Antibody binds inhibitory receptor (e.g., PD‑1) → prevents ligand interaction → restores NFAT/NF‑κB signaling → cytokine production resumes. --- 🔍 Key Comparisons CD4⁺ helper vs CD8⁺ cytotoxic MHC restriction: CD4⁺ → MHC II; CD8⁺ → MHC I. Primary role: CD4⁺ → activate B cells, macrophages, other T cells; CD8⁺ → directly kill infected/tumor cells. Positive vs Negative Selection Positive: low‑affinity self‑MHC binding → survival → lineage choice. Negative: high‑affinity self‑antigen binding → apoptosis or Treg conversion. Exhausted vs Anergic T cells Exhausted: chronic antigen, high inhibitory receptors, partial function, reversible with checkpoint blockade. Anergic: lack of co‑stimulation, functional inactivation, usually irreversible without cytokine rescue. Checkpoint Inhibitor vs Conventional Immunosuppression Inhibitor: lifts brakes → boosts immunity (cancer, chronic infection). Immunosuppression: adds brakes → prevents graft rejection, autoimmunity. --- ⚠️ Common Misunderstandings “All Tregs arise from negative selection.” – Only a subset of strongly self‑reactive thymocytes become FOXP3⁺ Tregs; most are deleted. “Exhausted T cells are dead.” – They are alive but functionally impaired; they can be reinvigorated with checkpoint blockade. “CD28 is only expressed on naive T cells.” – Activated and memory T cells also retain CD28, though expression can be down‑regulated in chronic stimulation. “MHC class I presents only viral peptides.” – It presents any intracellular peptide, including self, tumor, and bacterial peptides. --- 🧠 Mental Models / Intuition “Goldilocks selection” – Thymocytes must bind self‑MHC just right: too weak → death by neglect; too strong → deletion or Treg conversion. “Two‑key lock” – TCR is key 1; CD28‑B7 is key 2. Both must turn to unlock full activation; missing key leaves the lock in a “jammed” (anergic) state. “Exhaustion as a dimmer switch” – Chronic stimulation slowly turns down cytokine production and cytotoxicity, rather than an on/off switch. --- 🚩 Exceptions & Edge Cases γδ T cells: recognize non‑peptide antigens (e.g., phospho‑antigens) and do not undergo classic positive/negative selection. NKT cells: respond to glycolipids presented by CD1d, not classical MHC. Peripheral Treg induction: naive CD4⁺ T cells can become FOXP3⁺ Tregs in the periphery under tolerogenic cytokine milieu (e.g., TGF‑β). Memory T‑cell subsets: central memory cells retain CCR7 → home to lymph nodes; tissue‑resident cells stay in peripheral tissues and do not recirculate. --- 📍 When to Use Which Diagnosing T‑cell deficiency → assess CD4⁺ and CD8⁺ counts; severe combined immunodeficiency (SCID) if both low. Choosing checkpoint therapy → high PD‑1/TIM‑3 co‑expression → consider anti‑PD‑1 ± anti‑TIM‑3. Managing transplant tolerance → aim to promote T‑cell exhaustion or expand Tregs; avoid strong checkpoint blockade. Selecting activation markers → early activation (within hours): CD69; proliferation (days): CD25 up‑regulation. --- 👀 Patterns to Recognize MHC‑restriction pattern: CD4⁺ → peptide‑MHC II; CD8⁺ → peptide‑MHC I. Exhaustion pattern: ↑ inhibitory receptors and ↓ cytokine output (IL‑2, IFN‑γ). Selection pattern in thymus: DN → DP → SP (single‑positive) with checkpoint (positive vs negative) dictated by affinity. Signal cascade pattern: TCR → Lck → ZAP‑70 → LAT → PLC‑γ → Ca²⁺/DAG → NFAT/NF‑κB/AP‑1 → IL‑2 transcription. --- 🗂️ Exam Traps “All CD8⁺ T cells are cytotoxic.” – Some CD8⁺ cells can have regulatory functions (e.g., CD8⁺ Tregs). “Negative selection eliminates all self‑reactive cells.” – A small fraction becomes Tregs; complete elimination would cause autoimmunity. “PD‑1 blockade always cures cancer.” – Only works when tumor‑infiltrating T cells are exhausted; some tumors lack PD‑L1 or have other immune evasion mechanisms. “Absence of co‑stimulation only causes apoptosis.” – It causes functional anergy, not immediate cell death. “Memory T cells are always CD45RO⁺.” – While common, some memory subsets (e.g., tissue‑resident) have distinct surface phenotypes (CD103⁺). ---