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Essential Requirement for Nicastrin in Marginal Zone and B-1 B Cell Development

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Essential Requirement for Nicastrin in Marginal Zone and B-1 B Cell Development Essential requirement for nicastrin in marginal zone and B-1 B cell development Jin Huk Choia,b,1,2, Jonghee Hanc,1, Panayotis C. Theodoropoulosa,d, Xue Zhonga, Jianhui Wanga, Dawson Medlera, Sara Ludwiga, Xiaoming Zhana, Xiaohong Lia, Miao Tanga, Thomas Gallaghera, Gang Yuc, and Bruce Beutlera,2 aCenter for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; bDepartment of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; cDepartment of Neuroscience, Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390; and dDepartment of Internal Medicine, Physician Scientist Training Program, Washington University in St. Louis, Barnes Jewish Hospital, St. Louis, MO 63110 Contributed by Bruce Beutler, January 7, 2020 (sent for review September 24, 2019; reviewed by Douglas J. Hilton and Ellen V. Rothenberg) γ-secretase is an intramembrane protease complex that catalyzes peritoneal cavity, and are maintained by self-renewal throughout the proteolytic cleavage of amyloid precursor protein and Notch. the life of the organism (10). It is well established that the spleen is Impaired γ-secretase function is associated with the development also required for B-1 (especially B-1a) cell development (11); of Alzheimer’s disease and familial acne inversa in humans. In a however, the underlying mechanism(s) that mediate B-1 cell dif- forward genetic screen of mice with N-ethyl-N-nitrosourea-induced ferentiation remain largely unknown. mutations for defects in adaptive immunity, we identified animals The γ-secretase protease complex cleaves multiple type I mem- within a single pedigree exhibiting both hypopigmentation of brane proteins, including amyloid precursor protein (APP) and the fur and diminished T cell-independent (TI) antibody responses. Notch. APP undergoes proteolytic processing by either α-or The causative mutation was in Ncstn, an essential gene encoding β-secretase to release soluble APP ectodomains into the extra- the protein nicastrin (NCSTN), a member of the γ-secretase complex cellular space. Then γ-secretase cleaves the remaining membrane- that functions to recruit substrates for proteolysis. The missense anchored APP C-terminal fragments (APP-CTFs) and generates mutation severely limits the glycosylation of NCSTN to its mature p3 (the byproduct of α-andγ-secretase cleavages) or amyloid β form and impairs the integrity of the γ-secretase complex as well as peptides (the byproduct of β- and/or γ-secretase cleavage) together its catalytic activity toward its substrate Notch, a critical regulator of with the APP intracellular domain (12). Notch plays essential roles B cell and T cell development. Strikingly, however, this missense in thymic T cell lineage commitment (13), as well as in specifica- IMMUNOLOGY AND INFLAMMATION mutation affects B cell development but not thymocyte or T cell tion of MZ B cell versus B-2 cell fate (14), and it undergoes a development. The Ncstn allele uncovered in these studies reveals series of proteolytic cleavages by ADAM family metalloproteases an essential requirement for NCSTN during the type 2 transitional- and γ-secretase to generate the Notch intracellular domain (NICD) marginal zone precursor stage and peritoneal B-1 B cell develop- (15). The γ-secretase complex consists of four core subunits: ment, the TI antibody response, fur pigmentation, and intestinal presenilin (PS), PS enhancer 2 (PEN-2), anterior pharynx-defective homeostasis in mice. 1 (APH-1), and nicastrin (16). Nicastrin is a type I membrane protein with a large extracellular domain (17) that functions as nicastrin | marginal zone B cells | B-1 B cells | T cell-independent antibody response Significance cell responses to antigens are classified as T cell-dependent Follicular B cells generally require T cell help to contribute to B(TD) or T cell-independent (TI) based on their need for adaptive immunity, producing several isotypes of immuno- T cell help in antibody production. Antigens eliciting a TD an- globulins that carry out distinct effector functions. Two spe- tibody response are proteins that are processed and presented to cialized B cell subsets, marginal zone (MZ) and B-1 B cells, arise helper T cells in the context of MHC II molecules. The TD from different developmental steps and have different func- antibody responses are mediated by follicular B cells (also known tions. They become activated to produce antibodies without as B-2 cells, the major B cell subset in the body) and are long- T cell help and are the major sources of plasma IgM. We identi- lasting to deploy high-affinity antibodies of multiple isotypes. In fied a viable missense allele of Ncstn in a forward genetic contrast, TI antigens, such as bacterial capsular polysaccharides screen. We discovered that the development of MZ and B-1 and viral capsids, stimulate antibody responses that do not require B cells, TI antibody response, fur pigmentation, and intestinal MHC II-restricted T cell help (1). The TI antibody response is homeostasis critically depend on the glycosylation status of mediated by the marginal zone (MZ) and B-1 B cell populations, NCSTN and the catalytic activity of γ-secretase toward its sub- which expand on immunization in extrafollicular sites (2–4) and strate Notch, a critical receptor in numerous developmental confer protective immunity by producing antigen-specific IgM decisions. without somatic hypermutation (4–7). Thus, TI responses give rise to less specific but more immediate protection compared with Author contributions: J.H.C., J.H., P.C.T., G.Y., and B.B. designed research; J.H.C., J.H., TD antibody responses. P.C.T., X. Zhong, and J.W. performed research; D.M., S.L., X. Zhan, X.L., and M.T. contrib- uted new reagents/analytic tools; J.H.C., J.H., P.C.T., G.Y., and B.B. analyzed data; B-2 cells are continuously replenished from precursors in bone and J.H.C., J.H., T.G., G.Y., and B.B. wrote the paper. marrow, where they undergo both positive and negative selection. Reviewers: D.J.H., Institute of Medical Research; and E.V.R., California Institute of Immature B cells in bone marrow migrate to the spleen, where Technology. they differentiate through two transitional stages and become The authors declare no competing interest. mature naïve B-2 cells (8) or, alternatively, MZ B cells. Their fate Published under the PNAS license. is determined during the transitional stages and depends on signals 1J.H.C. and J.H. contributed equally to this work. κ from the B cell receptor, B cell activating factor, nuclear factor 2To whom correspondence may be addressed. Email: [email protected] or light chain enhancer of activated B cells, and Notch2, as well as [email protected]. signals involved in anatomical retention of MZ B cells in the This article contains supporting information online at https://www.pnas.org/lookup/suppl/ spleen (9). In contrast, B-1 cells are generated mainly from fetal doi:10.1073/pnas.1916645117/-/DCSupplemental. liver progenitors rather than bone marrow precursors, reside in the www.pnas.org/cgi/doi/10.1073/pnas.1916645117 PNAS Latest Articles | 1of8 Downloaded by guest on September 27, 2021 a γ-secretase substrate receptor (18). Activation of the γ-secretase screens, we identified several mice from a single pedigree complex requires extensive N-linked glycosylation of nicastrin, exhibiting hypopigmentation of the fur (Fig. 1A) and diminished which helps stabilize the protein (19). Mutations in γ-secretase TI antibody responses to (4-hydroxy-3-nitrophenyl) acetyl-Ficoll complex proteins and impaired catalytic activity of the complex (NP-Ficoll) compared with wild-type C57BL/6J mice (Fig. 1B). have been implicated in Alzheimer’s disease (AD) (20), fa- The mice exhibited comparable TD antibody responses to alumi- milial type acne inversa (21), hypopigmentation (22, 23), and num hydroxide-precipitated ovalbumin (OVA/alum; Fig. 1C). The thymic hypoplasia (24); however, little is known about the role phenotype, named truffle, was transmitted as a recessive trait. By and function of the γ-secretase complex in B cell-mediated automated meiotic mapping (25), the truffle phenotype was cor- immunity. Here we describe the effect of a severely hypomor- related with a missense mutation in Ncstn (Fig. 1D), resulting in a phic but viable missense mutation of Ncstn on MZ B cell and valine (V)-to-glycine (G) substitution at position 439 (V439G) in B-1 B cell development. the DYIGS and peptidase homologous (DAP) domain of the NCSTN protein (Fig. 1E)(18),whichwaspredictedtobedam- Results aging by PolyPhen-2 (score = 1.000) (26). Identification of a Viable Ncstn Missense Mutation. To identify genes To verify causation, CRISPR/Cas9-mediated gene targeting was required for the development and function of adaptive immu- used to generate a single nucleotide replacement allele (A→Cat nity, we carried out a forward genetic screen in third-generation chr1_172,070,009), causing the same amino acid change as that (G3) C57BL/6J mice bred to carry homozygous and heterozy- caused by the ENU-induced mutation (V439G). Consistent with gous mutations induced by N-ethyl-N-nitrosourea (ENU) in their truffle mice, NcstnV439G/V439G mice showed hypopigmentation of the great-grandsires (G0). During the course of adaptive immunity fur (Fig. 1F) and diminished TI and normal TD antibody responses, A B CD 4 4 10 m) m) Ncstn Wild-type truffle n -10 0 8 p=5.35 ×10 3 3 ) 45 10 6 @ -log 2 D 2 4 truffle truffle G (O 1 1 -value ( 2 P 0 NP IgM (OD0 @ 450 n 0 OVA Ig 123 45679 8 10 11131817 19 X WT G3 WT G3 Genomic location E SP DAP domain TM 132 134 273 498 669 691708 V439G (truffle) FGH I J V439G/ 4 4 110 ** 8 ** +/+ V439G m) *** n 0 cm) 100 ( 7 3 45 3 @ 2 D 2 90 6 al body weight i G (O M(OD@450nm) 1 1 80 5 Colon length %init NP Ig 0 0 70 4 V439G/ OVA Ig +/+ V439G/ +/+ V439G/ +/+ V439G/ +/+ V439G V439G V439G V439G +/+ males (n=18) KL+/+ females (n=22) 50 V439G/V439G males (n=29) V439G/V439G females (n=40) 40 + / + 30 l prolapse 20 10 %Recta V439G V439G/ 0 02479121416 Age (months) Fig.
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