Step 1 · Immunology

T-Cell Development & Activation

Name: T-Cell Development & Activation
Creator: Veli Bakalov, MD

Selection in the thymus, two signals to activate, and the checkpoints we now drug

Immunology·Adaptive·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Thymic maturation: double negative (CD4−CD8−) → double positive (CD4+CD8+) in the cortex → single positive (CD4+ or CD8+) in the medulla.
Positive selection (cortex): thymocytes must bind self-MHC or die, producing MHC restriction; negative selection (medulla): high-affinity self-reactive cells are deleted, producing central tolerance.
AIRE drives medullary self-antigen expression; AIRE mutation → APECED (autoimmune polyendocrinopathy with candidiasis, hypoparathyroidism, adrenal insufficiency).
Rule of 8: CD4 binds MHC II and CD8 binds MHC I; CD8 cells kill by perforin, granzymes, and Fas–FasL.
Activation needs signal 1 (TCR + antigen–MHC) and signal 2 (B7/CD80-86 on the APC + CD28); signal 1 alone causes anergy; IL-2 then drives clonal expansion.
Th1 (IL-12 → IFN-γ, IL-2; T-bet) fights intracellular pathogens; Th2 (IL-4 → IL-4, IL-5, IL-10, IL-13; GATA3) drives IgE and eosinophils; Th17 (IL-17; ROR-γt) recruits neutrophils; Treg (FOXP3, CD25; IL-10, TGF-β) maintains tolerance.
FOXP3 mutation → IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked).
Superantigens (TSST-1, streptococcal pyrogenic exotoxin A) cross-link MHC II to TCR Vβ outside the peptide groove, activating up to ~20% of T cells → cytokine storm and toxic shock.
CTLA-4 outcompetes CD28 for B7 (blocked by ipilimumab); PD-1/PD-L1 causes exhaustion (nivolumab, pembrolizumab, atezolizumab); blockade causes immune-related colitis, dermatitis, thyroiditis, pneumonitis.

T-cell development in the thymus

Maturation sequence. T-cell progenitors leave the bone marrow and enter the thymus as double-negative cells (CD4−CD8−). In the cortex they rearrange their TCR genes and become double-positive (CD4+CD8+); after selection they mature into single-positive cells (CD4+ or CD8+) in the medulla before leaving for the periphery.

Double negativeCD4− CD8−; arrive from marrow
Double positiveCD4+ CD8+; cortex
Positive selectionCortex: must bind self-MHC
Negative selectionMedulla: self-reactive cells deleted
Single positiveCD4+ or CD8+; exit to periphery

Thymic maturation

Positive selection (cortex). Only thymocytes whose TCR can bind self-MHC survive; the rest die by apoptosis ("death by neglect"). This step ensures MHC restriction — mature T cells recognize antigen only when it sits in self-MHC.

Negative selection (medulla). Thymocytes that bind self-antigen with HIGH affinity are deleted, establishing central tolerance; some are diverted into regulatory T cells instead. The transcription factor AIRE drives medullary expression of tissue-restricted self-antigens (such as endocrine proteins) so self-reactive clones can be found. An AIRE mutation causes APECED (autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy): chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency.

Thymic selection

Feature	Positive selection	Negative selection
Site	Cortex	Medulla
Question asked	Can the TCR see self-MHC?	Does the TCR bind self-antigen too strongly?
Fate of failures	Apoptosis if no binding	Deleted if high-affinity binding
Purpose	MHC restriction	Central tolerance
Linked defect	MHC II deficiency (bare lymphocyte syndrome): CD4 cells cannot be selected	AIRE mutation → APECED

Positive = cortex (can you see self-MHC?); Negative = medulla (don't attack self).

MHC restriction and two-signal activation

CD4 vs CD8. CD4 helper T cells recognize antigen on MHC II and help B cells and macrophages through cytokines. CD8 cytotoxic T cells recognize antigen on MHC I and kill infected cells. Rule of 8: CD4 × MHC-2 = 8 and CD8 × MHC-1 = 8.

Two signals. Full T-cell activation requires both. Signal 1: the TCR binds antigen–MHC, with CD4 or CD8 as co-receptor and CD3 transducing the signal. Signal 2 (costimulation): B7 (CD80/86) on the APC binds CD28 on the T cell. Signal 1 without signal 2 causes anergy — a built-in safeguard of peripheral tolerance, since only activated APCs express much B7.

Signal 1TCR + antigen–MHC
Signal 2B7 (CD80/86) + CD28
IL-2 releasedAutocrine growth signal via the IL-2 receptor (CD25)
Clonal expansionEffector + memory T cells

Two-signal activation

Drugging the signals. Calcineurin inhibitors (cyclosporine, tacrolimus) block IL-2 transcription after signal 1, and CTLA-4–Ig fusion proteins (abatacept, belatacept) block B7 costimulation — both used to suppress unwanted T-cell responses.

CD8 effector killing. Cytotoxic T cells kill virus-infected and tumor cells by inducing apoptosis through perforin and granzymes and through Fas–FasL. Full CD8 activation is helped by IL-2 from CD4 Th1 cells.

Helper T-cell subsets

Th1. Induced by IL-12 (and IFN-γ); secrete IFN-γ and IL-2; activate macrophages and CD8 T cells for defense against intracellular pathogens. Inhibited by IL-4 and IL-10 from Th2. IL-12 receptor defects abolish the Th1/IFN-γ axis and cause disseminated mycobacterial infection.

Th2. Induced by IL-4; secrete IL-4, IL-5, IL-10, and IL-13; recruit eosinophils and drive IgE and B-cell help (allergy, antihelminth immunity). Inhibited by IFN-γ from Th1. IL-4 drives the IgE class switch; IL-5 drives eosinophils and supports IgA production.

Th17 and Treg. Th17 cells are induced by IL-1, IL-6, IL-23, and TGF-β and secrete IL-17 to recruit neutrophils for mucosal defense against extracellular bacteria and fungi. Regulatory T cells are FOXP3+ CD4+ CD25+ and secrete IL-10 and TGF-β to maintain peripheral tolerance.

CD4 helper subsets

Subset	Induced by	Transcription factor	Secretes	Main job
Th1	IL-12, IFN-γ	T-bet	IFN-γ, IL-2	Macrophage and CD8 activation; intracellular pathogens
Th2	IL-4	GATA3	IL-4, IL-5, IL-10, IL-13	IgE, eosinophils; allergy, helminths
Th17	IL-1, IL-6, IL-23, TGF-β	ROR-γt	IL-17	Neutrophil recruitment; mucosal bacteria and fungi
Treg	TGF-β, IL-2	FOXP3	IL-10, TGF-β	Tolerance, suppression

Th1 and Th2 cross-inhibit each other: IFN-γ blocks Th2; IL-4 and IL-10 block Th1.

FOXP3 defect = IPEX: Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked — the peripheral-tolerance counterpart of AIRE's central-tolerance APECED.

Superantigens

Polyclonal activation. Superantigens — TSST-1 of S. aureus and streptococcal pyrogenic exotoxin A — cross-link MHC II directly to the TCR Vβ region OUTSIDE the peptide groove. Because no specific peptide is required, a large fraction of T cells (up to ~20%) is activated at once, releasing massive IL-2, IFN-γ, and TNF: a cytokine storm causing toxic shock with high fever, hypotension, and a diffuse rash that later desquamates.

Immune checkpoints and their inhibitors

CTLA-4. Expressed on activated T cells and Tregs, CTLA-4 binds B7 with HIGHER affinity than CD28, outcompeting it and delivering an inhibitory signal that dampens activation. Ipilimumab blocks CTLA-4 to unleash antitumor T cells.

PD-1. PD-1 on T cells binds PD-L1 on tumor cells and APCs, delivering an inhibitory "exhaustion" signal. Nivolumab and pembrolizumab (anti-PD-1) and atezolizumab (anti-PD-L1) restore antitumor immunity.

Checkpoint targets

Feature	CTLA-4	PD-1 / PD-L1
Ligand	B7 (competes with CD28)	PD-L1 on tumor cells and APCs
Effect	Dampens early activation	T-cell exhaustion in tissues
Blocking drugs	Ipilimumab	Nivolumab, pembrolizumab (PD-1); atezolizumab (PD-L1)

Releasing the brakes breaks tolerance: immune-related adverse events include colitis, dermatitis, thyroiditis, and pneumonitis.