ImmunologyTier 2Medical Sciences concept

T-cell activation - signal 1/2/3 model (TCR-MHC, costimulation, cytokines)

Core concept

Signal 1 - antigen specificity
- TCR + CD3 complex recognises peptide-MHC; CD4 or CD8 is the co-receptor binding the invariant MHC region
- -> Lck -> ZAP-70 -> LAT -> three arms: PLC-gamma -> Ca2+ -> calcineurin -> NFAT; DAG -> PKC -> NF-kB; Ras -> MAPK -> AP-1
- -> IL-2 transcription
Signal 2 - costimulation, the "licence"
- CD28 on the T cell binds CD80 (B7.1) / CD86 (B7.2) on the APC
- B7 is only expressed once the APC has itself been activated through a PRR -> the innate system licenses the adaptive system
- *Signal 1 without signal 2 -> ANERGY (or deletion), not activation* - a core mechanism of peripheral tolerance
Signal 3 - cytokines determine the lineage
- IL-12 -> Th1; IL-4 -> Th2; IL-6 + TGF-beta -> Th17; TGF-beta + IL-2 -> Treg; IL-2 drives clonal expansion in all
CD28 and CTLA-4 bind the same ligands with opposite effect
- CTLA-4 has ~10-100x higher affinity for CD80/86, is upregulated after activation, and is constitutively high on Tregs
- -> CTLA-4 outcompetes CD28 and strips B7 off the APC by trans-endocytosis -> shuts activation down
B-cell help uses the same logic: thymus-dependent (protein) antigens need BCR engagement + CD40 on the B cell binding CD40L on the activated helper T cell -> germinal centre, class switching, memory
- Thymus-independent (polysaccharide) antigens skip this - hence no memory and poor responses in children under 2

Costimulatory and coinhibitory pairs

Receptor (T cell)	Ligand (APC)	Effect
CD28	CD80/CD86	Activating - signal 2
CTLA-4 (CD152)	CD80/CD86	Inhibitory - early, lymph node, sets the activation threshold
PD-1 (CD279)	PD-L1/PD-L2	Inhibitory - late, in peripheral tissue and tumour, limits effector function
ICOS	ICOS-L	Activating; Tfh differentiation and B-cell help
CD40L (CD154)	CD40 (B cell, DC, macrophage)	T-cell help; licenses the DC; class switching
OX40, 4-1BB, GITR	ligands	Activating (survival)
LAG-3, TIM-3, TIGIT	MHC II, galectin-9, CD155	Inhibitory - exhaustion markers

Where the drugs act

Signal	Drug	Mechanism
1	Ciclosporin (binds cyclophilin), tacrolimus (binds FKBP12)	Both inhibit calcineurin -> NFAT stays cytoplasmic -> dec IL-2, IL-3, IL-4, IFN-gamma, TNF
1	Anti-thymoglobulin, alemtuzumab (CD52), muromonab (CD3)	T-cell depletion
2	Belatacept / abatacept - CTLA-4-Ig fusion proteins	Bind B7 -> block CD28 -> no signal 2
2	Ipilimumab (anti-CTLA-4), nivolumab/pembrolizumab (anti-PD-1)	Release the brake -> enhance T-cell activity against tumour
3	Basiliximab (anti-CD25/IL-2Ralpha), sirolimus/everolimus (mTOR), tofacitinib (JAK)	Block IL-2 signalling and downstream proliferation
3	Mycophenolate, azathioprine	Block lymphocyte nucleotide synthesis -> no clonal expansion

Calcineurin inhibitor practicalities
- Both nephrotoxic; both CYP3A4 and P-gp substrates -> multiple interactions (azoles, macrolides, diltiazem raise levels; rifampicin, phenytoin, St John's wort lower them)
- Ciclosporin: gum hypertrophy, hirsutism, hypertension > tacrolimus
- Tacrolimus: neurotoxicity (tremor, PRES), post-transplant diabetes, alopecia > ciclosporin
- Monitor tacrolimus trough (C0); ciclosporin monitored by trough or C2 peak
- Higher exposure early, minimised later - the standard strategy

Belatacept - equivalent efficacy to ciclosporin without nephrotoxicity, better long-term GFR
- *Contraindicated in EBV-seronegative recipients - high risk of EBV-driven post-transplant lymphoproliferative disease, especially CNS PTLD*
Abatacept - RA, PsA, JIA; the therapeutic version of the CTLA-4 checkpoint
Checkpoint inhibitors are the same biology inverted - and their toxicity profile follows the physiology
- Anti-CTLA-4 acts in the lymph node -> broader, earlier, more severe irAEs (colitis, hypophysitis)
- Anti-PD-1/PD-L1 acts in tissue -> organ-specific, later (thyroiditis, pneumonitis, hepatitis)
CTLA-4 haploinsufficiency and LRBA deficiency - the human knockouts: lymphoproliferation, autoimmune cytopenias, enteropathy, hypogammaglobulinaemia; treated with abatacept
CD40L deficiency = X-linked hyper-IgM - normal/high IgM, no class switching, and PJP because the CD40 signal also licenses macrophages and DCs
Superantigens (TSST-1, streptococcal exotoxin) bypass signal 1 specificity by cross-linking the TCR Vbeta region to MHC II outside the groove -> massive polyclonal activation -> toxic shock syndrome
Anergy and exhaustion underlie tumour immune escape and chronic viral infection - the rationale for checkpoint blockade and for CAR-T design

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