STEPTRACKERIMMUNOLOGY | ADAPTIVE IMMUNITY | HIGH-YIELD REVIEW

T-Cell Activation & Subsets

A naive T cell needs antigen plus a second signal to wake up; the cytokines around it then decide which job — Th1, Th2, Th17, Tfh or Treg — it takes on.

FOCUS ON
Activation: signal 1 = TCR + CD4/CD8 binds peptide–MHC; signal 2 = CD28 ↔ B7 (CD80/86); then IL-2 drives proliferation (calcineurin → NFAT, blocked by cyclosporine/tacrolimus). Without signal 2 → anergy. Subsets: Th1 (IL-12 → T-bet → IFN-γ; macrophages, intracellular microbes, granulomas, type IV), Th2 (IL-4 → GATA3 → IL-4, IL-5, IL-13; IgE, eosinophils, helminths, allergy), Th17 (IL-6 + TGF-β, IL-23 → RORγt → IL-17, IL-22; neutrophils, fungi, extracellular bacteria; psoriasis, IBD), Tfh (IL-21, CD40L; germinal centers), Treg (TGF-β, IL-2 → FOXP3 → IL-10, TGF-β; CD25). CD8⁺ killing: perforin, granzyme, Fas–FasL. IFN-γ inhibits Th2; IL-4/IL-10 inhibit Th1.
SUBSET
INDUCED BY · TRANSCRIPTION FACTOR
SECRETES · TARGETS
DISEASE LINK
Th1
IL-12 (macrophages, DCs), IFN-γ · T-bet
IFN-γ, IL-2 → activates macrophages, CD8⁺ cells, IgG opsonizing antibodies
Granulomas (TB, sarcoid), type IV HSR · IL-12/IFN-γ defects → mycobacteria
Th2
IL-4 · GATA3
IL-4 (IgE switch), IL-5 (eosinophils), IL-13 (mucus, IgE)
Asthma, atopy, helminths · dupilumab (IL-4Rα), mepolizumab (IL-5)
Th17
IL-6 + TGF-β; IL-23 maintains · RORγt
IL-17, IL-22 → neutrophil recruitment, epithelial defense
Psoriasis, IBD, ankylosing spondylitis · STAT3 defect (hyper-IgE) → Candida, S aureus · secukinumab, ustekinumab
Tfh
IL-6, IL-21 · BCL-6
IL-21, CD40L → germinal center B cells
Class switching, affinity maturation
Treg
TGF-β, IL-2 · FOXP3 (CD4⁺CD25⁺)
IL-10, TGF-β, CTLA-4 → suppress immune responses
IPEX (FOXP3) · IL-2 receptor (CD25) deficiency
CD8⁺ cytotoxic T cell
MHC I + IL-2
Perforin, granzyme B; FasL → apoptosis; IFN-γ
Viral infection, tumors, graft rejection, type 1 diabetes
Signal 1
TCR–CD3 recognizes peptide on MHC; CD4/CD8 bind MHC
—
Without signal 2 → anergy
Signal 2
CD28 on T cell + B7 (CD80/86) on APC
Also CD40L–CD40 licenses APCs
Abatacept, belatacept (CTLA-4-Ig) block it
IL-2 signaling
Calcineurin → NFAT → IL-2 gene; IL-2R → mTOR → proliferation
Autocrine growth
Tacrolimus/cyclosporine (calcineurin) · sirolimus (mTOR) · basiliximab (IL-2R)
Checkpoints
CTLA-4 (outcompetes CD28), PD-1 (with PD-L1)
Shut down activated T cells
Ipilimumab, nivolumab → immune-related adverse events
Memory T cells
Central (nodes) and effector memory (tissues)
Faster, larger secondary response
Basis of vaccination

Picture it — helper T-cell fates

Naive CD4⁺T cellTh1IL-12T-betIFN-γmacrophages · intracellularTh2IL-4GATA3IL-4, IL-5, IL-13IgE, eosinophils, helminthsTh17IL-6 + TGF-β, IL-23RORγtIL-17, IL-22neutrophils, fungi, barriersTfhIL-6, IL-21BCL-6IL-21, CD40Lgerminal-center B cellsTregTGF-β, IL-2FOXP3IL-10, TGF-βsuppression, tolerancesubset (inducing cytokine)TFproduct → target
CD4⁺ subsetsThe cytokines present at activation switch on a master transcription factor; each subset then makes its own cytokines and recruits a different effector.

Schematic diagrams, not to scale.

Mechanism — how CD8⁺ cells kill

TCR binds peptide–MHC I
→
Immunologic synapseGranules polarize
→
Perforin makes poresGranzyme B enters
→
Caspases → apoptosisAlso FasL–Fas

Cross-regulation

CYTOKINE
PROMOTES
INHIBITS
IL-12
Th1
—
IFN-γ
Th1, macrophages
Th2, Th17
IL-4
Th2, IgE
Th1
IL-10
Treg function
Th1, macrophages
TGF-β
Treg, Th17 (with IL-6)
Most T cells

How it's tested

COMMON CONFUSIONIL-12 (made by macrophages, drives Th1) vs IL-2 (made by T cells, drives T-cell proliferation) vs IFN-γ (made by Th1/NK, activates macrophages).
THE TRAPA patient with recurrent mycobacterial and Salmonella infections may have a defect in the IL-12 receptor or IFN-γ receptor, not HIV.
YOUR APPROACHInfection or disease type → subset that handles it → inducing cytokine and transcription factor → product → drug that targets it.

If you see… think…

Costimulatory pair for naive T cells → CD28 and B7
Antigen without costimulation → anergy
Granulomas and macrophage activation → Th1 (IFN-γ)
Eosinophils and IgE in helminth infection → Th2 (IL-4, IL-5, IL-13)
Neutrophil recruitment, psoriasis plaques → Th17 (IL-17)
Transcription factor of Tregs → FOXP3
Germinal center help via IL-21 → Tfh
Calcineurin inhibitor target gene → IL-2 (via NFAT)
Pores and granzyme-mediated killing → CD8⁺ T cell or NK cell
Disseminated BCG with IFN-γ receptor mutation → Th1 axis defect