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T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation

Nature Immunology volume 9, pages 282–291 (2008)Cite this article

Abstract

After homing to lymph nodes, CD8+ T cells are primed by dendritic cells (DCs) in three phases. During phase one, T cells undergo brief serial contacts with DCs for several hours, whereas phase two is characterized by stable T cell–DC interactions. We show here that the duration of phase one and T cell activation kinetics correlated inversely with the number of complexes of cognate peptide and major histocompatibility complex (pMHC) per DC and with the density of antigen-presenting DCs per lymph node. Very few pMHC complexes were necessary for the induction of full-fledged T cell activation and effector differentiation. However, neither T cell activation nor transition to phase two occurred below a threshold antigen dose determined in part by pMHC stability. Thus, phase one permits T cells to make integrated 'measurements' of antigen dose that determine subsequent T cell participation in immune responses.

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Figure 1: Interactions of P14 T cells with DCs pulsed with C-peptide or M-peptide in vivo.
Figure 2: Number of cognate pMHC complexes on DCs.
Figure 3: Peptide dose dependence of T cell activation.
Figure 4: Dose-dependent effects of C-peptide and M-peptide on T cell–DC interaction dynamics in vivo.
Figure 5: Effect of antigen dose on the meandering of T cells in lymph nodes.
Figure 6: Tissue concentration of cognate antigen–bearing DCs controls T cell proliferation and IFN-γ production.
Figure 7: Early phase two for antigen-specific T cells interacting with threshold dose antigen-pulsed DCs when a second DC population pulsed with high-dose antigen is also in the lymph node.
Figure 8: DCs can simultaneously maintain phase one– and phase two–like interactions with two different T cell populations.

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Acknowledgements

We thank T. Buschman for assistance with programming; M. van den Broek for providing cDNA constructs for the P14 TCR; and G. C heng and J. Alton for technical and secretarial assistance, respectively. Supported by the National Institutes of Health (AI069259 and AI072252 to U.H.v.A.; HL07623 and Medical Scientist Training Program to S.E.H.; HL066987 to T.R.M.; PO1 AI071195-01 for H.Z., M.N.A. and A.K.C.).

Author information

Authors and Affiliations

  1. Department of Pathology and the Immune Disease Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Sarah E Henrickson, Thorsten R Mempel, Irina B Mazo, Antonio Peixoto, Michael P Flynn, Balimkiz Senman, Tobias Junt & Ulrich H von Andrian

  2. Altor BioScience, Miramar, Florida, 33025, USA

    Bai Liu & Hing C Wong

  3. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Maxim N Artyomov & Arup K Chakraborty

  4. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Huan Zheng & Arup K Chakraborty

  5. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Arup K Chakraborty

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  1. Sarah E Henrickson
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Contributions

S.E.H. designed the study, did and analyzed experiments, and wrote the manuscript; U.H.v.A designed the study and wrote the manuscript; T.R.M., I.B.M., A.P., M.P.F., B.S. and T.J. did experiments; B.L. and H.C.W. provided reagents; and M.N.A., H.Z. and A.K.C. modeled the experimental data.

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Correspondence to Ulrich H von Andrian.

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Competing interests

H.C.W. is president and CEO of Altor BioScience and B.L. is a senior scientist at Altor Bioscience.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Methods (PDF 1676 kb)

Supplementary Video 1

Phase one with high dose C-peptide. Antigen-specific P14 T cells (green) and control OT-I T cells (blue) interacted with 10μM C-peptide pulsed CD11c+ DCs (red). The peptide-pulsed DCs (20μM CMTMR) were injected with 10ng LPS into the footpad of a recipient C57BL6 mouse. 18 hours later, P14 CD8+ T cells (2.5μM CMFDA, green) and control, OT-I CD8+ T cells (10μM CMAC, blue) were injected i.v. followed 2h later by 100mg Mel-14 antibody i.v. Images were collected from 2.5-3.5h after T cell transfer by MPM-IVM of the right popliteal LN in an anesthetized mouse in the z dimension over a distance of 40μm. Bar = 10μm. (MOV 7727 kb)

Supplementary Video 2

Early phase two with high dose M-peptide. (MOV 8663 kb)

Antigen-specific P14 T cells (green) and control OT-I T cells (blue) interacted with 10μM M-peptide pulsed CD11c+ DCs (red). The peptide-pulsed DCs (20μM CMTMR) were injected with 10ng LPS into the footpad of a recipient C57BL6 mouse. 18 hours later, P14 CD8+ T cells (2.5μM CMFDA, green) and control, OT-I CD8+ T cells (10μM CMAC, blue) were injected i.v. followed 2h later by 100μg Mel-14 antibody i.v.. Images were collected from 2.5-3.5h after T cell transfer by MPM-IVM of the right popliteal LN in an anesthetized mouse in the z dimension over a distance of 40μm. Bar = 10μm.

Supplementary Video 3

Phase one with a sub-threshold dose of M-peptide. (MOV 8229 kb)

Antigen-specific P14 T cells (green) and control OT-I T cells (blue) interacted with 100pM M-peptide pulsed CD11c+ DCs (red). The peptide-pulsed DCs (20μM CMTMR) were injected with 10ng LPS into the footpad of a recipient C57BL6 mouse. 18 hours later, P14 CD8+ T cells (2.5μM CMFDA, green) and control, OT-I CD8+ T cells (10μM CMAC, blue) were injected i.v. followed 2h later by 100μg Mel-14 antibody i.v.. Images were collected from 2.5-3.5h after T cell transfer by MPM-IVM of the right popliteal LN in an anesthetized mouse in the z dimension over a distance of 40μm. Bar = 10μm.

Supplementary Video 4

Prolonged phase one with a threshold dose of M-peptide. (MOV 8624 kb)

Antigen-specific P14 T cells (green) and control OT-I T cells (blue) interacted with 200pM M-peptide pulsed CD11c+ DCs (red). The peptide-pulsed DCs (20μM CMTMR) were injected with 10ng LPS into the footpad of a recipient C57BL6 mouse. 18 hours later, P14 CD8+ T cells (2.5μM CMFDA, green) and control, OT-I CD8+ T cells (10μM CMAC, blue) were injected i.v. followed 2h later by 100mg Mel-14 antibody i.v.. Images were collected from 2.5-3.5h after T cell transfer by MPM-IVM of the right popliteal LN in an anesthetized mouse in the z dimension over a distance of 40μm. Bar = 10μm.

Supplementary Video 5

Late phase two with a threshold dose of M-peptide. (MOV 8829 kb)

Antigen-specific P14 T cells (green) and control OT-I T cells (blue) interacted with 200pM M-peptide pulsed CD11c+ DCs (red). The peptide-pulsed DCs (20μM CMTMR) were injected with 10ng LPS into the footpad of a recipient C57BL6 mouse. 18 hours later, P14 CD8+ T cells (2.5μM CMFDA, green) and control, OT-I CD8+ T cells (10μM CMAC, blue) were injected i.v. followed 2h later by 100mg Mel-14 antibody i.v.. Images were collected from 6.5-7.5h after T cell transfer by MPM-IVM of the right popliteal LN in an anesthetized mouse in the z dimension over a distance of 40μm. Bar = 10μm.

Supplementary Video 6

Early phase two with very high dose C-peptide.Antigen-specific P14 T cells (green) and control OT-I T cells (blue) interacted with 100μM C-peptide pulsed CD11c+ DCs (red). The peptide-pulsed DCs (20μM CMTMR) were injected with 10ng LPS into the footpad of a recipient C57BL6 mouse. 18 hours later, P14 CD8+ T cells (2.5μM CMFDA, green) and control, OT-I CD8+ T cells (10μM CMAC, blue) were injected i.v. followed 2h later by 100mg Mel-14 antibody i.v.. Images were collected from 4-5h after T cell transfer by MPM-IVM of the right popliteal LN in an anesthetized mouse in the z dimension over a distance of 40μm. Bar = 10μm. (MOV 7933 kb)

Supplementary Video 7

Earlier phase two for P14 interacting with two populations of DCs pulsed with different levels of M-peptide. (MOV 6674 kb)

Antigen-specific P14 T cells (green) interacted with two populations of peptide pulsed CD11c+ DCs (red: 200pM M-peptide, blue: 10μM M-peptide). The peptide-pulsed DCs (red, 20μM CMTMR and blue, 10μM CMAC) were injected with 10ng LPS into the footpad of a recipient C57BL6 mouse. 18 hours later, P14 CD8+ T cells (2.5μM CMFDA) were injected i.v. followed 2h later by 100mg Mel-14 antibody i.v.. Images were collected from 4-5h after T cell transfer by MPM-IVM of the right popliteal LN in an anesthetized mouse in the z dimension over a distance of 40μm. Bar = 10μm.

Supplementary Video 8

Phase one for P14 T cells and phase two for OT-I T cells interacting with dually peptide pulsed DCs. (MOV 6035 kb)

Antigen-specific P14 T cells (green) and control OT-I T cells (blue) interacted with dually peptide pulsed CD11c+ DCs (red, 200pM M-peptide and 10μM SIINFEKL). The peptide-pulsed DCs (20μM CMTMR) were injected with 10ng LPS into the footpad of a recipient C57BL6 mouse. 18 hours later, P14 CD8+ T cells (2.5μM CMFDA, green) and control, OT-I CD8+ T cells (10μM CMAC, blue) were injected i.v. followed 2h later by 100mg Mel-14 antibody i.v.. Images were collected from 3.5-4.5h after T cell transfer by MPM-IVM of the right popliteal LN in an anesthetized mouse in the z dimension over a distance of 40μm. Bar = 10μm.

Supplementary Video 9

Phase two for both P14 T cells and OT-I T cells interacting with dually peptide pulsed DCs. (MOV 8650 kb)

Antigen-specific P14 T cells (green) and control OT-I T cells (blue) interacted with dually peptide pulsed CD11c+ DCs (red, 10nM M-peptide and 10μM SIINFEKL). The peptide-pulsed DCs (20μM CMTMR) were injected with 10ng LPS into the footpad of a recipient C57BL6 mouse. 18 hours later, P14 CD8+ T cells (2.5μM CMFDA, green) and control, OT-I CD8+ T cells (10μM CMAC, blue) were injected i.v. followed 2h later by 100mg Mel-14 antibody i.v.. Images were collected from 2.5-3.5h after T cell transfer by MPM-IVM of the right popliteal LN in an anesthetized mouse in the z dimension over a distance of 40μm. Bar = 10μm.

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Henrickson, S., Mempel, T., Mazo, I. et al. T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nat Immunol 9, 282–291 (2008). https://doi.org/10.1038/ni1559

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