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Cytokine-secreting follicular T cells shape the antibody repertoire

Nature Immunology volume 10, pages 385–393 (2009)Cite this article

Abstract

High-affinity antibodies are critical for host protection and underlie successful vaccines. The generation of such antibodies requires T cell–dependent help, which mediates germinal center reactions in which mutation and selection of B cells occurs. Using an interleukin 4–reporter system, we show here that CD4+ follicular helper T cells constituted essentially all of the cytokine-secreting T cells in lymph nodes and were functionally distinct from T cells secreting the same cytokine in peripheral tissues. Follicular helper T cells with different cytokine profiles could be isolated as conjugates with B cells undergoing cytokine-specific immunoglobulin class switching with evidence of somatic hypermutation. Our findings support a model in which B cells compete for cytokines produced by follicular helper T cells that shape the affinity and isotype of the antibody response.

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Figure 1: Kinetics and identification of IL-4-producing cells in draining lymph nodes after infection with L. major.
Figure 2: IL-4-producing cells in the lymph nodes of 4get-KN2 mice coexpress ICOS, CXCR5 and huCD2 after L. major infection.
Figure 3: ICOS regulates IL-4 production by TFH cells.
Figure 4: IL-4-producing CD4 T cells in lymph nodes are TFH cells and are functionally distinct from canonical TH2 cells.
Figure 5: B cell–T cell conjugates regulate immunoglobulin class switching.
Figure 6: Somatic hypermutation in the JH4 intron and VH186.2 region.
Figure 7: Function of IL-4-producing TFH cells in the generation and affinity maturation of plasma cells.

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Acknowledgements

We thank G. Kelsoe (Duke University), M. Nussenzweig (Rockefeller University), K. McBride (Rockefeller University) and A. N. McKenzie (Trinity College, Dublin) for reagents and suggestions; J. Cyster, A. DeFranco and C. Allen for review and comments; and N. Flores, L. Stowring and C. McArthur for technical expertise. Supported by the National Institutes of Allergy and Infectious Diseases (AI026918 and AI077439), the Howard Hughes Medical Institute, the Sandler Asthma Basic Research Center of the University of California San Francisco and the Juvenile Diabetes Research Foundation–Irvington Institute (R.L.R.).

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  1. Howard Hughes Medical Institute and Departments of Medicine and Microbiology & Immunology, University of California San Francisco, San Francisco, California, USA

    R Lee Reinhardt, Hong-Erh Liang & Richard M Locksley

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  1. R Lee Reinhardt
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Contributions

R.L.R. and R.M.L. conceived the work; R.L.R. designed, did and analyzed experiments for Figures 1, 2, 3, 4, 5 and 7; R.L.R. helped do and analyze Figure 6; H.-E.L. designed, did and analyzed experiments for Figures 5 and 6; R.M.L. designed experiments; R.L.R and R.M.L. wrote the manuscript; and all authors read and provided comments on the manuscript.

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Correspondence to Richard M Locksley.

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Reinhardt, R., Liang, HE. & Locksley, R. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol 10, 385–393 (2009). https://doi.org/10.1038/ni.1715

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