TY - JOUR
T1 - Lunatic, manic, and radical fringe each promote T and B cell development
AU - Song, Yinghui
AU - Kumar, Vivek
AU - Wei, Hua Xing
AU - Qiu, Ju
AU - Stanley, Pamela
N1 - Funding Information:
This work was supported by National Institutes of Heath Grants NCI RO1 95022 and NIGMS RO1 GM106417 (to P.S.) and the Albert Einstein Cancer Center (National Cancer Institute Grant PO1 13333). We thank Susan Cole (University of Ohio) for providing mice carrying mutant alleles of Lfng, Mfng, and Rfng; Cynthia Guidos (University of Toronto and Hospital for Sick Children) for helpful comments; and Wen Dong, Huimin Shang, and Subha Sundaram for technical assistance.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Lunatic, Manic, and Radical Fringe (LFNG, MFNG, and RFNG) are N-acetylglucosaminyltransferases that modify Notch receptors and regulate Notch signaling. Loss of LFNG affects thymic T cell development, and LFNG and MFNG are required for marginal zone (MZ) B cell development. However, roles for MFNG and RFNG in T cell development, RFNG in B cell development, or Fringes in T and B cell activation are not identified. In this study, we show that Lfng/Mfng/Rfng triple knockout (Fng tKO) mice exhibited reduced binding of DLL4 Notch ligand to CD4/CD8 double-negative (DN) T cell progenitors, and reduced expression of NOTCH1 targets Deltex1 and CD25. Fng tKO mice had reduced frequencies of DN1/cKit+ and DN2 T cell progenitors and CD4+CD8+ double-positive (DP) T cell precursors, but increased frequencies of CD4+ and CD8+ single-positive T cells in the thymus. In spleen, Fng tKO mice had reduced frequencies of CD4+, CD8+, central memory T cells and MZ B cells, and an increased frequency of effector memory T cells, neutrophils, follicular, and MZ P B cells. The Fng tKO phenotype was cell-autonomous and largely rescued in mice expressing one allele of a single Fng gene. Stimulation of Fng tKO splenocytes with anti-CD3/CD28 beads or LPS gave reduced proliferation compared with controls, and the generation of activated T cells by Concanavalin A or L-PHA was also reduced in Fng tKO mice. Therefore, each Fringe contributes to Tand B cell development, and Fringe is required for optimal in vitro stimulation of T and B cells.
AB - Lunatic, Manic, and Radical Fringe (LFNG, MFNG, and RFNG) are N-acetylglucosaminyltransferases that modify Notch receptors and regulate Notch signaling. Loss of LFNG affects thymic T cell development, and LFNG and MFNG are required for marginal zone (MZ) B cell development. However, roles for MFNG and RFNG in T cell development, RFNG in B cell development, or Fringes in T and B cell activation are not identified. In this study, we show that Lfng/Mfng/Rfng triple knockout (Fng tKO) mice exhibited reduced binding of DLL4 Notch ligand to CD4/CD8 double-negative (DN) T cell progenitors, and reduced expression of NOTCH1 targets Deltex1 and CD25. Fng tKO mice had reduced frequencies of DN1/cKit+ and DN2 T cell progenitors and CD4+CD8+ double-positive (DP) T cell precursors, but increased frequencies of CD4+ and CD8+ single-positive T cells in the thymus. In spleen, Fng tKO mice had reduced frequencies of CD4+, CD8+, central memory T cells and MZ B cells, and an increased frequency of effector memory T cells, neutrophils, follicular, and MZ P B cells. The Fng tKO phenotype was cell-autonomous and largely rescued in mice expressing one allele of a single Fng gene. Stimulation of Fng tKO splenocytes with anti-CD3/CD28 beads or LPS gave reduced proliferation compared with controls, and the generation of activated T cells by Concanavalin A or L-PHA was also reduced in Fng tKO mice. Therefore, each Fringe contributes to Tand B cell development, and Fringe is required for optimal in vitro stimulation of T and B cells.
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U2 - 10.4049/jimmunol.1402421
DO - 10.4049/jimmunol.1402421
M3 - Article
C2 - 26608918
AN - SCOPUS:84953314268
SN - 0022-1767
VL - 196
SP - 232
EP - 243
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -