Medservatory
USMLE Step 1ImmunologyEP 02 of 14

T-cell activation: the two-signal model

A T cell can recognise its antigen perfectly and still stay asleep. T-cell activation needs a second signal, and the antigen-presenting cell decides whether it is given.

  • 4:58 video
  • 3 min read
  • 7 sources
  • Published 15 Nov 2026
Video lesson · 4:58 · Watch on YouTubeSeries: Immunology · @medservatory
Chapters (9)
By the end of this lesson

Explain the two-signal model of T-cell activation (signal one: TCR with peptide–MHC; signal two: CD28 with B7) and why signal one without signal two causes anergy.

The short version

  1. Signal one is the T-cell receptor binding peptide on MHC, with CD3 passing the message inside; it gives specificity.
  2. Signal two is costimulation: CD28 on the T cell binds B7-1 (CD80) or B7-2 (CD86) on the antigen-presenting cell.
  3. Signals one and two together make the T cell produce interleukin-2, divide, survive and differentiate.
  4. Signal one without signal two causes anergy, a safety lock that is part of peripheral tolerance.
  5. CTLA-4 binds B7 with much higher affinity than CD28 but sends no activating signal, so it brakes the response.

Why T cells that see self do not attack

Every day, tissues shed fragments of their own proteins, and dendritic cells carry them to lymph nodes. Some T cells that escaped the thymus can bind those self fragments perfectly. Yet they do not attack.

The answer is the two-signal model of T-cell activation. Recognising an antigen is only the first step; a second, confirming signal decides whether the T cell switches on.[1][3]

Signal one: the T-cell receptor reads the antigen

A naive T cell has never met its antigen. Its T-cell receptor (TCR) binds a peptide held on an MHC molecule, and the CD3 complex passes the message into the cell. That is signal one.[1][3][7]

CD4 or CD8 binds a separate region of MHC and holds the contact steady. Signal one gives specificity: it tells the T cell what the antigen is.[1][3]

Signal two: CD28 and B7 costimulation

Signal two is costimulation. CD28 on the T cell binds B7 molecules on the antigen-presenting cell: B7-1, also called CD80, and B7-2, also called CD86.[3][7]

Signal one plus signal two switches the T cell on. It makes interleukin-2 (IL-2), divides, survives and differentiates.[1][3]

The two signals compared
On the T cellOn the antigen-presenting cellWhat it gives
Signal oneTCR with CD3; CD4 or CD8Peptide on MHCSpecificity
Signal twoCD28B7-1 (CD80), B7-2 (CD86)Costimulation: the go-ahead

The antigen-presenting cell decides whether signal two exists

A resting dendritic cell in healthy tissue carries self fragments to the lymph node too, but with few B7 molecules.[4]

When a dendritic cell senses a microbe through its toll-like receptors, it raises B7 and other costimulatory molecules and carries the antigen to the lymph node. So costimulation is provided by an activated antigen-presenting cell.[2][4]

Signal one without signal two: anergy and peripheral tolerance

Signal one without signal two causes anergy: the T cell becomes unresponsive.[1][3]

Anergy is a safety lock and part of peripheral tolerance. A self antigen on a resting antigen-presenting cell gives signal one alone, so a self-reactive T cell that escaped the thymus is switched off instead of switched on.[1][3]

Two cases compared
  1. Healthy skin: a resting dendritic cell picks up a self protein, so there is signal one only → anergy
  2. Splinter wound with bacteria: a dendritic cell senses the microbe, raises B7 and presents a bacterial peptide, so a T cell specific for that peptide gets signal one and signal two → activation

The brake: CTLA-4 and ipilimumab

The system also has a brake. CTLA-4 is a relative of CD28 that binds B7 with much higher affinity, but it does not send an activating signal.[3]

Strong stimulation moves CTLA-4 to the T-cell surface, and regulatory T cells carry it constantly. B7 is mopped up and the response is limited.[3]

Blocking that brake with the antibody ipilimumab boosts anti-tumour T-cell activity in melanoma.[3]

T-cell activation: three things to keep

  1. Signal oneThe T-cell receptor with peptide on MHC. This gives specificity and tells the T cell what the antigen is; CD28 with B7 must then give signal two.[3]
  2. Signal one aloneWithout signal two the T cell becomes anergic, unresponsive, and does not mount an attack.[1][3]
  3. CTLA-4It binds B7 and brakes the response, because it has much higher affinity than CD28 and sends no activating signal.[3]

Next in the series are the helper T-cell subsets and the cytokines that shape them.

Practice question

Original · USMLE style
Your turnQB-MS-S1-IMM-009-01

A 48-year-old woman with rheumatoid arthritis has persistent joint swelling despite treatment with methotrexate. She is started on a soluble fusion protein made of the extracellular domain of CTLA-4 joined to the Fc portion of human IgG1.

This drug most directly prevents which of the following interactions?
Pick one option. Your answers stay on this device.

Common questions

What are the two signals in T-cell activation?

Signal one is the T-cell receptor binding peptide on MHC, which gives specificity. Signal two is costimulation, in which CD28 on the T cell binds B7 (CD80 or CD86) on the antigen-presenting cell.

What is anergy?

Anergy is a state in which the T cell becomes unresponsive. It follows signal one without signal two, and it is part of peripheral tolerance.

Which molecules provide costimulation in T-cell activation?

CD28 on the T cell binds B7-1 (CD80) or B7-2 (CD86) on the antigen-presenting cell. This is signal two.

How does the antigen-presenting cell control signal two?

A resting dendritic cell has few B7 molecules. When it senses a microbe through toll-like receptors, it raises B7 and other costimulatory molecules.

What does CTLA-4 do?

CTLA-4 is a CD28 relative that binds B7 with much higher affinity but sends no activating signal. It limits the response; the antibody ipilimumab blocks it and boosts anti-tumour T-cell activity in melanoma.

Transcript

Read the full narration, by chapter657 words

0:00The puzzle: T cells that bind self fragments yet do not attack

Every day your tissues shed fragments of your own proteins, and dendritic cells carry them to lymph nodes. Some T cells that escaped the thymus can bind those self fragments perfectly. Yet they do not attack. What stops them? Today: the two signal model of T cell activation, and why signal one alone leaves a T cell asleep.

0:22Signal one: TCR with peptide on MHC, CD3 and the co-receptor, and why it is not enough

A naive T cell has never met its antigen. Its T cell receptor binds a peptide on an MHC molecule, and the CD three complex passes the message inside. That is signal one. CD four or CD eight holds the contact steady. Signal one gives specificity: it tells the T cell what the antigen is. But specificity alone is not enough to start an attack. Signal two is costimulation.

0:51Signal two: costimulation, CD28 binds B7 (CD80 and CD86)

A receptor on the T cell, CD 28, binds B seven molecules on the antigen-presenting cell: B seven one, also called CD 80, and B seven two, called CD 86. Signal one plus signal two switches the T cell on. The T cell makes interleukin two, divides, survives and differentiates.

1:16The antigen-presenting cell decides: toll-like receptors raise B7

Now the clever part: the antigen-presenting cell decides whether signal two exists. A resting dendritic cell in healthy tissue carries self fragments to the lymph node too, but with few B seven molecules. When it senses a microbe through its toll-like receptors, it raises B seven and other costimulatory molecules, and carries the antigen to the lymph node.

1:40Signal one alone: anergy and peripheral tolerance, two cases compared

Signal one without signal two causes anergy: the T cell becomes unresponsive. That is a safety lock, part of peripheral tolerance, because a self antigen on a resting antigen-presenting cell gives signal one alone. Compare two cases. A resting dendritic cell picks up a self protein from healthy skin: signal one only, so anergy. A splinter wound with bacteria: signal one and signal two, so activation.

2:13The brake: CTLA-4, regulatory T cells, ipilimumab

The system also has a brake. CTLA four is a CD 28 relative that binds B seven with much higher affinity, but it does not send an activating signal. Strong stimulation moves CTLA four to the T cell surface, and regulatory T cells carry it constantly, so B seven is mopped up and the response is limited. Blocking that brake with the antibody ipilimumab boosts anti-tumour T cell activity in melanoma.

2:43Practice question

Your turn. A 48-year-old woman with rheumatoid arthritis has persistent joint swelling despite methotrexate. She starts a soluble fusion protein made of the extracellular domain of CTLA four joined to the Fc portion of human I g G one. This drug most directly prevents which of the following interactions? A, CD 28 on the T cell binding CD 80 and CD 86 on the antigen-presenting cell. B, CD 40 ligand on the T cell binding CD 40 on the antigen-presenting cell. C, the T cell receptor binding peptide in MHC class two on the antigen-presenting cell. D, CD four on the T cell binding MHC class two on the antigen-presenting cell. E, PD one on the T cell binding PDL one on the antigen-presenting cell.

3:41Answer: the wrong options first, then the correct one

Pause here and decide. B is out: CD 40 ligand and CD 40 are a different pair, and the drug binds B seven, not CD 40. C is out: the T cell receptor and its peptide are signal one, which the drug does not touch. D is out: the co-receptor grips MHC class two itself, and the drug does not bind it. E is out: PD one is a separate inhibitory pathway, with its own ligands. So the answer is A. The CTLA four part binds B seven on the antigen-presenting cell, so CD 28 cannot receive signal two, and the T cell gets signal one without it.

4:30Recap pocket card and next lesson

Three things to keep. One: signal one is the T cell receptor with peptide on MHC; signal two is CD 28 with B seven. Two: signal one alone causes anergy. Three: CTLA four binds B seven and brakes the response. Next, the helper T cell subsets and the cytokines that shape them.

Sources

Numbers in the text, e.g. [1], point here
  1. OpenStax Microbiology 18.3: T Lymphocytes and Cellular Immunity. openstax.org/books/microbiology/pages/18-3-t-lymphocytes-and-cellular-immunity
  2. OpenStax Microbiology 18.2: Major Histocompatibility Complexes and Antigen-Presenting Cells. openstax.org/books/microbiology/pages/18-2-major-histocompatibility-complexes-and-antigen-presenting-cells
  3. Europe PMC open-access reviews (two-signal model, CD28, B7, CTLA-4, ipilimumab, PD-1): europepmc.org/article/PMC/PMC4892769 · europepmc.org/article/PMC/PMC2118836 · europepmc.org/article/PMC/PMC13205506 · europepmc.org/article/PMC/PMC2193311
  4. Europe PMC (dendritic cell maturation, toll-like receptors, B7 levels): europepmc.org/article/PMC/PMC2213015 · europepmc.org/article/PMC/PMC12587171 · europepmc.org/article/PMC/PMC13486443
  5. Europe PMC (CTLA-4 Fc fusion protein, rheumatoid arthritis): europepmc.org/article/PMC/PMC2927615 · europepmc.org/article/PMC/PMC5561378 · europepmc.org/article/PMC/PMC2564802 · europepmc.org/article/PMC/PMC10154649
  6. Europe PMC (CD40 ligand and CD40): europepmc.org/article/PMC/PMC3580555 · europepmc.org/article/PMC/PMC11322596
  7. Background: en.wikipedia.org/wiki/CD28 · en.wikipedia.org/wiki/T-cell_receptor

The cells and molecules on screen are schematic and not to scale. The B7-level dials are qualitative, low versus high, with no numbers.

The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.

Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (recoloured, outlined, resized): skin, melanoma, rheumatoid arthritis hand, thymus. NIAID NIH BioArt Source (bioart.niaid.nih.gov), public domain: dendritic cell, T cell, TCR with MHC, MHC class II with CD4, CD28, CD80, CD86, CTLA-4, dendritic cell bound to regulatory T cells, toll-like receptor, lymph node. Icons via bioicons.com, adapted: TCR-CD3 (Margot Riggi, CC BY 4.0, https://creativecommons.org/licenses/by/4.0/), wound healing (Servier, CC BY 3.0, https://creativecommons.org/licenses/by/3.0/). Bacteria icon: Health Icons (CC0). The locks, B7-level dials, membranes, antibody, drug schematic, question card, pocket card and all handwriting are drawn in code (original). No AI-generated teaching images.

Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-IMM-009.

For exam study only, not medical advice. Read the medical disclaimer.

In this series

Playlist on YouTube
← Previous · EP 01MHC I vs MHC II: how antigen presentation works
  1. EP 01MHC I vs MHC II: how antigen presentation works5:03
  2. EP 02T-cell activation: the two-signal model4:58
  3. EP 03Th1, Th2, Th17 and Treg: helper T-cell subsets5:13
  4. EP 04Antibody isotypes and class switching5:13
  5. EP 05Central vs peripheral tolerance: how lymphocytes learn self-tolerance5:26
  6. EP 06Complement system explained: three pathways, one ending5:24
  7. EP 07Complement deficiencies: C1q, C3, C5–C9 and C1 inhibitor5:15
  8. EP 08Hypersensitivity types I to IV: the four effectors5:20
  9. EP 09B-cell vs T-cell immunodeficiency: predict the infections5:24
  10. EP 10Hyper IgM syndrome: CD40 ligand and class switching5:19
  11. EP 11Chronic granulomatous disease: NADPH oxidase and the respiratory burst5:20
  12. EP 12Leukocyte adhesion deficiency: CD18 and neutrophil extravasation5:01
  13. EP 13Transplant rejection explained: hyperacute, acute, chronic and GVHD5:51
  14. EP 14Vaccine types explained: live, inactivated, conjugate and mRNA5:41