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IL-2 Producing Memory CD4⁺ T Lymphocytes Are Closely Associated with the Generation of IgG-Secreting Plasma Cells¹

Nicolle H. R. Litjens^2,*, Martin Huisman^*, Daniëlle Hijdra, Bart M. N. Lambrecht, Koert J. Stittelaar and Michiel G. H. Betjes^*

^* Department of Internal Medicine, Division of Nephrology, Department of Pulmonary Diseases, and Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands

The role of specific CD4⁺ T cell subsets in the induction of humoral immune responses in humans is largely unknown. In this study, the generation of hepatitis B surface Ag-specific CD4⁺ T lymphocytes following vaccination was closely monitored and characterized at the single-cell level. The appearance and absolute numbers of hepatitis B surface Ag-specific IL-2 producing effector memory CD4⁺ T lymphocytes was solely and tightly related to Ab titers reached. This relation remained present many years after vaccination. Subsequently, a relation was found between Ab titers and number of IL-2 producing memory CD4⁺ T lymphocytes for various other Ags. These observations matched the findings of an in vitro assay, using different T cell subsets to induce B cell differentiation into IgG-producing plasma cells. By depleting for IL-2 producing memory T cells, we demonstrated that these cells are important for B cell differentiation into IgG-producing plasma cells. Finally, blocking the action of IL-2 with an IL-2R- Ab inhibited the differentiation of B lymphocytes into IgG-producing plasma cells. Based on these findings, we conclude that the development of Ag-specific IL-2-producing memory T cells appears to be essential for the development of IgG-secreting plasma cells in humans.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was financially supported by a grant from the Dutch Kidney Foundation (Grant no. 1630008) and the Malpighi Foundation.

² Address correspondence and reprint requests to Dr. Nicolle Litjens, Department of Internal Medicine, Division of Nephrology, Room Ee 551, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: n.litjens{at}erasmusmc.nl

³ Abbreviations used in this paper: HBV, hepatitis B virus; HBsAg, hepatitis B surface Ag; Tmem, total memory CD4⁺ T lymphocyte; ESRD, end-stage renal disease; moDC, monocyte-derived dendritic cell; Rs, Spearmans rho correlation coefficient; Tcm, central CD4⁺ T lymphocyte; Tem, effector CD4⁺ T lymphocyte.