APRIL modulates B and T cell immunity
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
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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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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Increased proliferation of T cells and survival of T cells from APRIL Tg...
Increased proliferation of T cells and survival of T cells from APRIL Tg mice in vitro. (a) Increased proliferation of Tg T cells after 2 days’ culturing with anti-CD3 alone, or anti-CD3 in combination with anti-CD28. (b) T cell response in APRIL Tg mice in vivo: Delayed deletion of superantigen-responsive Vβ8+ CD4+ cells in APRIL Tg mice. PBLs were stained for CD4, CD8, and Vβ8 on the days indicated (n = 4). This is one representative experiment of four performed. ANOVA confirmed that the differences for CD4+ cells at days 7, 10, and 13 are statistically significant (Table 2). *P < 0.05. The Vβ6+ subpopulation of CD4+ and CD8+ cells was unresponsive at all time points analyzed (not shown). (c and d) Survival of purified T cells cultured for 3 days alone, with anti-CD3, or with anti-CD3 plus anti-CD28. Cells were stained for CD4 (c) or CD8 (d) and PI as described in Methods. (e) Purified T cells of C57BL/6 mice were cultured for 2 days without stimulation, alone or in the presence of 5 μg/ml recombinant APRIL, and PI-stained. (f) Purified CD4+ T cells were cultured for 3 days without stimulation, alone or in the presence of 50 μg/ml of TACI-Fc, BMCA-Fc, or control Ig. Similar results were obtained for CD8+ T cells. All data in a and c–f are the mean ± SD of triplicate determinations of a representative experiment of at least three performed. The statistical significance of the data was determined using ANOVA.