T-cell activation: two signals and superantigens !

Process

A naive T cell needs to see its antigen and receive a second «go» signal; bacterial superantigens bypass this and switch on huge numbers of T cells.

Updated 2026-11-01

What it is

Activating a naive T cell requires signal 1 (the TCR recognizing peptide on MHC, with CD4 or CD8) and signal 2 (costimulation, mainly CD28 binding B7 on an activated antigen-presenting cell). Cytokines then shape what kind of effector the cell becomes. Without signal 2 the cell becomes anergic, which protects against autoimmunity. Superantigens skip specificity by linking MHC class II to many TCRs at once, causing a cytokine storm.

Key facts

Superantigens bind outside the peptide groove of MHC class II and to the variable part of the TCR beta chain, activating a large fraction of T cells.
Examples: toxic shock syndrome toxin-1 and enterotoxins of Staphylococcus aureus, and streptococcal pyrogenic exotoxins of Streptococcus pyogenes.
The result is massive release of IL-2, IFN-γ and TNF: fever, rash, hypotension and multiorgan failure.
CD8 T cells kill with perforin and granzymes or with Fas ligand.

Step by step

Signal 1: the TCR binds the specific peptide on MHC; CD4 binds class II or CD8 binds class I; CD3 transmits the signal.
Signal 2: CD28 on the T cell binds B7 (CD80/CD86) on an activated dendritic cell.
The T cell produces IL-2 and its high-affinity receptor chain CD25, and proliferates (clonal expansion).
Signal 3: cytokines from the antigen-presenting cell direct differentiation (for example IL-12 toward Th1).
Effector cells leave the lymph node; some become memory cells.
Brakes: CTLA-4 (binds B7 more strongly than CD28) and PD-1 shut the response down.
Signal 1 without signal 2 leads to anergy, a state of unresponsiveness.

Clinical notes

Toxic shock syndrome: high fever, sunburn-like rash that later peels on palms and soles, hypotension and organ failure.
Abatacept (CTLA-4 fused to an antibody fragment) blocks B7 and is used in rheumatoid arthritis.
Checkpoint inhibitors (anti-CTLA-4, anti-PD-1, anti-PD-L1) release the brakes against tumors and can cause immune-related adverse effects.
Calcineurin inhibitors such as cyclosporine and tacrolimus block IL-2 transcription after signal 1.

Test yourself

Think of the answer, then tap the question to see it.

What happens when a naive T cell receives signal 1 without costimulation?

It becomes anergic: functionally unresponsive, which is one mechanism of peripheral tolerance.

Which molecules provide the main costimulatory signal?

CD28 on the T cell binding B7-1 (CD80) or B7-2 (CD86) on the antigen-presenting cell.

How do superantigens activate so many T cells?

They bind MHC class II outside the peptide groove and the variable region of the TCR beta chain, cross-linking them regardless of the antigen the TCR recognizes.

Which bacteria produce the superantigens of toxic shock syndrome?

Staphylococcus aureus (TSST-1 and enterotoxins) and Streptococcus pyogenes (streptococcal pyrogenic exotoxins).

How does CTLA-4 turn off T-cell activation?

It binds B7 with higher affinity than CD28, taking away costimulation and delivering an inhibitory signal.

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Toxic shock syndrome

Microorganisms

In Pharmacology

Abatacept

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Educational content on the immune system; not a treatment or individual vaccination guide and no substitute for a health professional's advice. No doses are given.

Sources: 18.3 T Lymphocytes and Cellular Immunity (OpenStax (Microbiology), 2016); Toxic shock syndrome (MedlinePlus Medical Encyclopedia, U.S. National Library of Medicine, 2024); 21.3 The Adaptive Immune Response: T lymphocytes and Their Functional Types (OpenStax (Anatomy and Physiology 2e), 2022).

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Representative model, for educational purposes only.