APRIL modulates B and T cell immunity
Jens V. Stein, … , Jan Paul Medema, Michael Hahne
Jens V. Stein, … , Jan Paul Medema, Michael Hahne
Published June 15, 2002
Citation Information: J Clin Invest. 2002;109(12):1587-1598. https://doi.org/10.1172/JCI15034.
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Article Immunology

APRIL modulates B and T cell immunity

Abstract

The TNF-like ligands APRIL and BLyS are close relatives and share the capacity to bind the receptors TACI and BCMA. BLyS has been shown to play an important role in B cell homeostasis and autoimmunity, but the biological role of APRIL remains less well defined. Analysis of T cells revealed an activation-dependent increase in APRIL mRNA expression. We therefore generated mice expressing APRIL as a transgene in T cells. These mice appeared normal and showed no signs of B cell hyperplasia. Transgenic T cells revealed a greatly enhanced survival in vitro as well as enhanced survival of staphylococcal enterotoxin B–reactive CD4+ T cells in vivo, which both directly correlate with elevated Bcl-2 levels. Analysis of humoral responses to T cell–dependent antigens in the transgenic mice indicated that APRIL affects only IgM but not IgG responses. In contrast, T cell–independent type 2 (TI-2) humoral response was enhanced in APRIL transgenic mice. As TACI was previously reported to be indispensable for TI-2 antibody formation, these results suggest a role for APRIL/TACI interactions in the generation of this response. Taken together, our data indicate that APRIL is involved in the induction and/or maintenance of T and B cell responses.

Authors

Jens V. Stein, Marta López-Fraga, Fernando A. Elustondo, Carla E. Carvalho-Pinto, Dolores Rodríguez, Ruth Gómez-Caro, Joan de Jong, Carlos Martínez-A, Jan Paul Medema, Michael Hahne

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Figure 1

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(a) APRIL expression in activated, but not in naive, T cells. Activated ...
(a) APRIL expression in activated, but not in naive, T cells. Activated T cells have increased APRIL mRNA expression levels. DO11.10 spleen CD4+ T cells were isolated and activated in vitro toward a Th1 or Th2 phenotype. RNA was prepared from naive, Th1, and Th2 cells and used to analyze the expression of APRIL, BLyS, and GAPDH by RT-PCR. Generation and characterization of APRIL Tg mice. (b) Schematic diagram of constructs used for peripheral T cell–specific expression of the human APRIL transgene. (c) mRNA expression of APRIL in T cells of four different founders. RNA was prepared from purified T cells derived from spleen and lymph nodes of four Tg mice and analyzed by RT-PCR for APRIL RNA expression levels. To ensure that the amplified human APRIL signal was not due to contaminating genomic DNA, cDNA probes were amplified for Thy1 using primers that amplify a 300-bp fragment of cDNA and a 700-bp fragment of genomic DNA (genomic mouse DNA was used as control). (d) Protein expression of APRIL in Tg mouse T cells. Cell lysates were prepared from purified T cells derived from spleen and lymph nodes of four Tg mice, a control littermate, and a C57BL/6 mouse and analyzed in Western blot using anti-human APRIL antibodies (8). (e) Secreted APRIL circulates in serum of APRIL Tg mice. Sera (1 μl) of control and Tg mice were resolved under nonreducing conditions and immunoblots developed with anti-human APRIL antibodies. Recombinant (Rec.) APRIL protein (0.1–5 ng) added to control serum was used as standard.