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CD98hc facilitates B cell proliferation and adaptive humoral immunity

Nature Immunology volume 10, pages 412–419 (2009)Cite this article

Abstract

The proliferation of antigen-specific lymphocytes and resulting clonal expansion are essential for adaptive immunity. We report here that B cell–specific deletion of the heavy chain of CD98 (CD98hc) resulted in lower antibody responses due to total suppression of B cell proliferation and subsequent plasma cell formation. Deletion of CD98hc did not impair early B cell activation but did inhibit later activation of the mitogen-activated protein kinase Erk1/2 and downregulation of the cell cycle inhibitor p27. Reconstitution of CD98hc-deficient B cells with CD98hc mutants showed that the integrin-binding domain of CD98hc was required for B cell proliferation but that the amino acid–transport function of CD98hc was dispensable for this. Thus, CD98hc supports integrin-dependent rapid proliferation of B cells. We propose that the advantage of adaptive immunity favored the appearance of CD98hc in vertebrates.

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Figure 1: Deletion of CD98hc in Slc3a2f/fCD19-Cre+ mice.
Figure 2: Impaired antibody responses in Slc3a2f/fCD19-Cre+ mice.
Figure 3: Normal B cell distribution and natural antibody concentrations in Slc3a2f/fCD19-Cre+ mice.
Figure 4: Defective formation of plasma cells in Slc3a2f/fCD19-Cre+ mice.
Figure 5: Proliferation of splenic B cells from Slc3a2f/fCD19-Cre+ mice.
Figure 6: Mechanism by which CD98hc enables B cell proliferation.
Figure 7: Integrin signaling defects in B cells lacking CD98hc.
Figure 8: Selection for CD98hc+ B cells during activation.

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Acknowledgements

We thank M. Slepak for technical assistance; D. Rose for advice on analyzing antibody responses; M. Cato for advice and protocols for enzyme-linked immunospot assays; and R. Zent (Vanderbilt University) for Slc3a2+/− mice. Supported by the National Institutes of Health (AR27214, HL31950 and HL0780784), the Arthritis Foundation (C.C.F.) and the National Multiple Sclerosis Society (FG1802-A-1 to J.C.).

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Authors and Affiliations

  1. Department of Medicine, University of California San Diego, La Jolla, California, USA

    Joseph Cantor & Mark H Ginsberg

  2. Program of Inflammatory Disease Research, Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, La Jolla, California, USA

    Cecille D Browne & Robert C Rickert

  3. Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany

    Raphael Ruppert & Reinhard Fässler

  4. Institut National de la Santé et de la Recherche Médicale, Nice-Sophia Antipolis University, Nice, France

    Chloé C Féral

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Contributions

M.H.G., J.C. and C.C.F. conceived the project with advice and collaboration from R.C.R.; J.C. and M.H.G. wrote the manuscript with editorial input from R.C.R. and C.C.F.; R.C.R. provided CD19-Cre mice; J.C. did experiments except as follows: C.D.B. did immunohistochemical analysis of spleen sections and flow cytometry for B cell subsets, and R.R. tested B cell proliferation in pan integrin-deficient mice.

Corresponding authors

Correspondence to Robert C Rickert or Mark H Ginsberg.

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Cantor, J., Browne, C., Ruppert, R. et al. CD98hc facilitates B cell proliferation and adaptive humoral immunity. Nat Immunol 10, 412–419 (2009). https://doi.org/10.1038/ni.1712

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