Impaired IgA class switching in APRIL-deficient mice

Emanuela Castigli

Sumi Scott

Fatma Dedeoglu

Paul Bryce

^{Division of Immunology, Children's Hospital and Department of Pediatrics, and}^{Department of Pathology, Immunopathology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115}

^{To whom correspondence should be addressed. E-mail:}ude.dravrah.hct@aheg.fiar.

Communicated by Frederick W. Alt, Harvard Medical School, Boston, MA, January 14, 2004

Received 2003 Aug 21

Abstract

The tumor necrosis factor (TNF) family member APRIL binds to the receptors BCMA on B cells and TACI on B and T cells. To investigate the role of APRIL in immunity, we generated APRIL-deficient mice. APRIL^{mice have normal T and B lymphocyte development, normal T and B cell proliferation}in vitro, but increased numbers of CD44^CD62L^CD4^{effector/memory T cells and increased IgG responses to T-dependent antigens. Serum IgA levels were significantly decreased, and serum IgA antibody responses to mucosal immunization with TD antigens and to type 1 T-independent antigens were impaired in APRIL}^{mice. APRIL by itself induced IgA as well as IgG1 isotype switching in CD40-deficient IgM}^IgD^{sorted B cells. These results suggest that APRIL down-regulates T cell-dependent antibody responses and promotes IgA class switching.}

Abstract

APRIL (TNFSF 13a), also known as TALL-2 and TRDL-1, and BAFF (TNFSF 13b), also known as BLyS, TALL-1, THANK, and zTNF4, are two recently described members of the tumor necrosis factor (TNF) family of ligands (1). They have a similar genomic organization and exhibit 50% homology at the protein level. APRIL and BAFF are synthesized as type II transmembrane proteins with a TNF homology C-terminal domain that is characteristic of TNF family members (1). Both APRIL and BAFF are proteolytically cleaved into a soluble form at a multibasic motif by a furin-like protease. APRIL is cleaved intracellularly, then secreted (2). Heterotrimers of APRIL and BAFF that can stimulate human B cells have been described (3). A TWEAK-APRIL fusion protein, TWE-PRIL, in which the APRIL extracellular domain is fused to the intracellular, transmembrane and part of the extracellular domains of TWEAK, is also known to exist (4).

APRIL is highly expressed in tumor cell lines and at different levels in a variety of tissues, including human monocytes/macrophages, dendritic cells, T cells, murine bone marrow, and spleen (4-7). APRIL and BAFF both bind to two receptors, B cell maturation antigen (BCMA) and transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI), which are members of the TNF receptor (TNFR) family (8-13). BCMA is exclusively expressed on B cells (14, 15), whereas TACI is expressed on B cells and activated T cells (16). A third receptor, BAFF-R (or BR3), which is unique for BAFF, is expressed on B cells (17, 18). An APRIL-specific receptor has been postulated based on the observation that some tumor cell lines bind APRIL but not BAFF (10, 19).

BAFF enhances B cell survival and synergizes with B cell receptor crosslinking to induce B cell proliferation in vitro (20-23). Mice treated with soluble BAFF and BAFF transgenic mice show increased number of mature B cells and plasma cells, enlarged secondary lymphoid organs, increased levels of polyclonal serum immunoglobulins of all isotypes, and increased number of germinal centers (GCs) in the absence of immunization (22, 24, 25). BAFF transgenic mice developed high titers of autoantibodies and a systemic lupus erythematosus-like condition (24). BAFF^{mice have a severe defect in B cell development and virtually lack T}₂ immature B cells, marginal zone B cells, and mature B cells (26, 27). These studies suggest that BAFF plays an important role in B cell activation and survival and is required for the transition from T₁ to T₂ immature B cells.

APRIL has been found to cause modest proliferation of B and T cells and to synergize with B and T cell receptor crosslinking to induce B and T cell proliferation in vitro (13, 19). Administration of murine soluble APRIL to mice results in increased spleen weight and increased percentages of splenic B cells (13). However, expression of a human APRIL transgene in mouse T cells resulted in no signs of B cell hyperplasia, but enhanced T cell survival in vitro and survival of staphylococcal enterotoxin B-reactive Vβ8^CD4^{T cells}in vivo; both correlated with elevated Bcl-2 levels (7). IgM, but not IgG, responses to TD antigens were increased in APRIL transgenic mice. The antibody response to type 2 T-independent (TI-2) antigen was enhanced (7). However, the role of APRIL in the development and function of immune cells remains to be defined. To this purpose we have generated and characterized APRIL-deficient mice.

Acknowledgments

We thank Drs. A. Kettner, S. Brodeur, and J. P. Manis for critical review of the manuscript and A. Flint and Q. Vu for excellent technical assistance. This work was supported by National Institutes of Health Grants AI31136 (to R.S.G.), AI31541 (to R.S.G.), DK47677 (to A.K.B.), and DK43351 (to A.K.B.), the Jeffrey Modell Foundation, Baxter Healthcare, and Mr. Neal Wallace.

Acknowledgments

Notes

Abbreviations: TNF, tumor necrosis factor; BCMA, B cell maturation antigen; TACI, transmembrane activator and calcium modulator and cytophilin ligand interactor; GC, germinal center; TI-1, type 1 T-independent; TI-2, type 2 T-independent; ES, embryonic stem; GLT, germ-line transcripts; AID, activation-induced deaminase; LPS, lipopolysaccharide; TGF, transforming growth factor.

Notes

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