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Regulating T helper cell immunity through antigen responsiveness and calcium entry

Nature Immunology volume 1, pages 402–412 (2000)Cite this article

Abstract

We evaluated changes in the signaling potentials and proliferative capacity of single antigen–specific T helper (TH) cells during a primary immune response to a protein antigen. At the peak of cellular expansion in vivo all antigen-specific TH cells exhibited a profound block in CD3- and CD4-mediated mobilization of intracellular calcium together with a more global block in T cell receptor–independent capacitative calcium entry (CCE). The proliferative response of these antigen-specific TH cells to anti-CD3, anti-CD28 and IL-2 was also severely blunted. Cross-linking CD69 on a substantial fraction of CD69+ antigen–specific TH cells relieved this block in CCE and restored proliferative capacity in vitro. The CCE rescue operated through a CD69-coupled G protein and required calcium-bound calmodulin and calcineurin. These data reveal critical changes in the responsiveness of antigen-specific TH cells and provide evidence of new mechanisms for the regulation of antigen-specific TH cell development in vivo.

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Figure 1: Isolating PCC-specific TH cells directly ex vivo.
Figure 2: Block in CD3 and CD4 -mediated calcium response at day 7 in vivo .
Figure 3: Block in CCE at day 7.
Figure 4: Blunted proliferative capacity of day 7 PCC-specific TH cells.
Figure 5: Diminished responder frequency and extent of clonal expansion.
Figure 6: Block in CCE at day 5 in vivo.
Figure 7: CD69 rescues the block in TCR-independent CCE.
Figure 8: CCE rescue through Gαi protein, calmodulin and calcineurin.
Figure 9: CD69 restores proliferative capacity.

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Acknowledgements

We thank D. Driver, J. Fanelli Panus, J. Mikszta, A. Means, T. Meyer, T. Tedder and M. Krangel for comments on the manuscript; M. Davis and J. Altman for the gift of MCC–I-Ek tetramers; D. Patel (core facility of the Duke Specialized Center of Research in RA) and J. P. Allison for gifts of anti-CD28 and anti-CD3; E. Shevach for the H1.2F3 hybridoma; and the Duke Comprehensive Cancer Center Flow Cytometry Shared Resource and Confocal Microscopy Facility. Supported by a National Institutes of Health grant (AI40215), a post-doctoral fellowship (RRPC) and a Biomedical Sciences Grant (MMW) from the Arthritis Foundation.

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  1. Gabriel Bikah

    Present address: GlaxoWellcome, Research and Development, Research Triangle Park, NC, 27709, USA

  2. Rebecca R. Pogue-Caley

    Present address: MERIX Bioscience Inc., Research Triangle Park, NC, 27709, USA

  3. Gabriel Bikah and Rebecca R. Pogue-Caley: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Duke University Medical Center, Durham, 27710, NC, USA

    Gabriel Bikah, Rebecca R. Pogue-Caley, Louise J. McHeyzer-Williams & Michael G. McHeyzer-Williams

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Correspondence to Michael G. McHeyzer-Williams.

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Bikah, G., Pogue-Caley, R., McHeyzer-Williams, L. et al. Regulating T helper cell immunity through antigen responsiveness and calcium entry. Nat Immunol 1, 402–412 (2000). https://doi.org/10.1038/80841

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