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1.
PLoS Genet ; 19(7): e1010845, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37440598

RESUMO

Embryogenesis requires coordinated gene regulatory activities early on that establish the trajectory of subsequent development, during a period called the maternal-to-zygotic transition (MZT). The MZT comprises transcriptional activation of the embryonic genome and post-transcriptional regulation of egg-inherited maternal mRNA. Investigation into the MZT in animals has focused almost exclusively on bilaterians, which include all classical models such as flies, worms, sea urchin, and vertebrates, thus limiting our capacity to understand the gene regulatory paradigms uniting the MZT across all animals. Here, we elucidate the MZT of a non-bilaterian, the cnidarian Hydractinia symbiolongicarpus. Using parallel poly(A)-selected and non poly(A)-dependent RNA-seq approaches, we find that the Hydractinia MZT is composed of regulatory activities similar to many bilaterians, including cytoplasmic readenylation of maternally contributed mRNA, delayed genome activation, and separate phases of maternal mRNA deadenylation and degradation that likely depend on both maternally and zygotically encoded clearance factors, including microRNAs. But we also observe massive upregulation of histone genes and an expanded repertoire of predicted H4K20 methyltransferases, aspects thus far particular to the Hydractinia MZT and potentially underlying a novel mode of early embryonic chromatin regulation. Thus, similar regulatory strategies with taxon-specific elaboration underlie the MZT in both bilaterian and non-bilaterian embryos, providing insight into how an essential developmental transition may have arisen in ancestral animals.


Assuntos
Cnidários , RNA Mensageiro Estocado , Animais , RNA Mensageiro Estocado/genética , Cnidários/genética , Regulação da Expressão Gênica no Desenvolvimento , Zigoto/metabolismo , Desenvolvimento Embrionário/genética
2.
Proc Natl Acad Sci U S A ; 119(40): e2207374119, 2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36161920

RESUMO

Most colonial marine invertebrates are capable of allorecognition, the ability to distinguish between themselves and conspecifics. One long-standing question is whether invertebrate allorecognition genes are homologous to vertebrate histocompatibility genes. In the cnidarian Hydractinia symbiolongicarpus, allorecognition is controlled by at least two genes, Allorecognition 1 (Alr1) and Allorecognition 2 (Alr2), which encode highly polymorphic cell-surface proteins that serve as markers of self. Here, we show that Alr1 and Alr2 are part of a family of 41 Alr genes, all of which reside in a single genomic interval called the Allorecognition Complex (ARC). Using sensitive homology searches and highly accurate structural predictions, we demonstrate that the Alr proteins are members of the immunoglobulin superfamily (IgSF) with V-set and I-set Ig domains unlike any previously identified in animals. Specifically, their primary amino acid sequences lack many of the motifs considered diagnostic for V-set and I-set domains, yet they adopt secondary and tertiary structures nearly identical to canonical Ig domains. Thus, the V-set domain, which played a central role in the evolution of vertebrate adaptive immunity, was present in the last common ancestor of cnidarians and bilaterians. Unexpectedly, several Alr proteins also have immunoreceptor tyrosine-based activation motifs and immunoreceptor tyrosine-based inhibitory motifs in their cytoplasmic tails, suggesting they could participate in pathways homologous to those that regulate immunity in humans and flies. This work expands our definition of the IgSF with the addition of a family of unusual members, several of which play a role in invertebrate histocompatibility.


Assuntos
Hidrozoários , Imunoglobulinas , Complexo Principal de Histocompatibilidade , Animais , Hidrozoários/genética , Hidrozoários/imunologia , Imunoglobulinas/química , Imunoglobulinas/genética , Complexo Principal de Histocompatibilidade/genética , Proteínas de Membrana/química , Proteínas de Membrana/genética , Domínios Proteicos , Tirosina/química , Tirosina/genética
3.
BMC Biol ; 21(1): 32, 2023 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-36782149

RESUMO

BACKGROUND: Sex determination occurs across animal species, but most of our knowledge about its mechanisms comes from only a handful of bilaterian taxa. This limits our ability to infer the evolutionary history of sex determination within animals. RESULTS: In this study, we generated a linkage map of the genome of the colonial cnidarian Hydractinia symbiolongicarpus and used it to demonstrate that this species has an XX/XY sex determination system. We demonstrate that the X and Y chromosomes have pseudoautosomal and non-recombining regions. We then use the linkage map and a method based on the depth of sequencing coverage to identify genes encoded in the non-recombining region and show that many of them have male gonad-specific expression. In addition, we demonstrate that recombination rates are enhanced in the female genome and that the haploid chromosome number in Hydractinia is n = 15. CONCLUSIONS: These findings establish Hydractinia as a tractable non-bilaterian model system for the study of sex determination and the evolution of sex chromosomes.


Assuntos
Hidrozoários , Cromossomos Sexuais , Masculino , Feminino , Animais , Cromossomos Sexuais/genética , Mapeamento Cromossômico , Cromossomo Y/genética , Hidrozoários/genética , Evolução Molecular
4.
PLoS Biol ; 18(7): e3000811, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32735558

RESUMO

One of the earliest and most prevalent barriers to successful reproduction is polyspermy, or fertilization of an egg by multiple sperm. To prevent these supernumerary fertilizations, eggs have evolved multiple mechanisms. It has recently been proposed that zinc released by mammalian eggs at fertilization may block additional sperm from entering. Here, we demonstrate that eggs from amphibia and teleost fish also release zinc. Using Xenopus laevis as a model, we document that zinc reversibly blocks fertilization. Finally, we demonstrate that extracellular zinc similarly disrupts early embryonic development in eggs from diverse phyla, including Cnidaria, Echinodermata, and Chordata. Our study reveals that a fundamental strategy protecting human eggs from fertilization by multiple sperm may have evolved more than 650 million years ago.


Assuntos
Fertilização , Oócitos/metabolismo , Zinco/metabolismo , Ambystoma mexicanum , Animais , Feminino , Hidrozoários , Masculino , Strongylocentrotus purpuratus , Xenopus laevis , Peixe-Zebra
5.
Immunogenetics ; 74(1): 27-34, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34773127

RESUMO

Hydractinia symbiolongicarpus is a colonial hydroid and a long-standing model system for the study of invertebrate allorecognition. The Hydractinia allorecognition system allows colonies to discriminate between their own tissues and those of unrelated conspecifics that co-occur with them on the same substrate. This recognition mediates spatial competition and mitigates the risk of stem cell parasitism. Here, I review how we have come to our current understanding of the molecular basis of allorecognition in Hydractinia. To date, two allodeterminants have been identified, called Allorecognition 1 (Alr1) and Allorecognition 2 (Alr2), which occupy a genomic region called the allorecognition complex (ARC). Both genes encode highly polymorphic cell surface proteins that are capable of homophilic binding, which is thought to be the mechanism of self/non-self discrimination. Here, I review how we have come to our current understanding of Alr1 and Alr2. Although both are members of the immunoglobulin superfamily, their evolutionary origins remain unknown. Moreover, existing data suggest that the ARC may be home to a family of Alr-like genes, and I speculate on their potential functions.


Assuntos
Hidrozoários , Animais , Hidrozoários/genética , Imunoglobulinas
6.
BMC Genomics ; 19(1): 649, 2018 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-30176818

RESUMO

BACKGROUND: Hydractinia symbiolongicarpus, a colonial cnidarian, is a tractable model system for many cnidarian-specific and general biological questions. Until recently, tests of gene function in Hydractinia have relied on laborious forward genetic approaches, randomly integrated transgenes, or transient knockdown of mRNAs. RESULTS: Here, we report the use of CRISPR/Cas9 genome editing to generate targeted genomic insertions in H. symbiolonigcarpus. We used CRISPR/Cas9 to promote homologous recombination of two fluorescent reporters, eGFP and tdTomato, into the Eukaryotic elongation factor 1 alpha (Eef1a) locus. We demonstrate that the transgenes are expressed ubiquitously and are stable over two generations of breeding. We further demonstrate that CRISPR/Cas9 genome editing can be used to mark endogenous proteins with FLAG or StrepII-FLAG affinity tags to enable in vivo and ex vivo protein studies. CONCLUSIONS: This is the first account of CRISPR/Cas9 mediated knockins in Hydractinia and the first example of the germline transmission of a CRISPR/Cas9 inserted transgene in a cnidarian. The ability to precisely insert exogenous DNA into the Hydractinia genome will enable sophisticated genetic studies and further development of functional genomics tools in this understudied cnidarian model.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Técnicas de Introdução de Genes , Hidrozoários/genética , Fator 1 de Elongação de Peptídeos/genética , Animais , Vetores Genéticos , Recombinação Homóloga , Hidrozoários/crescimento & desenvolvimento , Transgenes
7.
J Immunol ; 186(4): 2633-42, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21257965

RESUMO

Several important events occur at the maternal-fetal interface, including generation of maternal-fetal tolerance, remodeling of the uterine smooth muscle and its spiral arteries and glands, and placental construction. Fetal-derived extravillous trophoblasts come in direct contact with maternal decidual leukocytes. Macrophages represent ∼20% of the leukocytes at this interface. In this study, two distinct subsets of CD14(+) decidual macrophages (dMs) are found to be present in first-trimester decidual tissue, CD11c(HI) and CD11c(LO). Gene expression analysis by RNA microarray revealed that 379 probes were differentially expressed between these two populations. Analysis of the two subsets revealed several clusters of coregulated genes that suggest distinct functions for these subsets in tissue remodeling, growth, and development. CD11c(HI) dMs express genes associated with lipid metabolism and inflammation, whereas CD11c(LO) dMs express genes associated with extracellular matrix formation, muscle regulation, and tissue growth. The CD11c(HI) dMs also differ from CD11c(LO) dMs in their ability to process protein Ag and are likely to be the major APCs in the decidua. Moreover, these populations each secrete both proinflammatory and anti-inflammatory cytokines that may contribute to the balance that establishes fetal-maternal tolerance. Thus, they do not fit the conventional M1/M2 categorization.


Assuntos
Antígeno CD11c/biossíntese , Decídua/imunologia , Decídua/metabolismo , Macrófagos/classificação , Macrófagos/imunologia , Biomarcadores/sangue , Antígeno CD11c/genética , Células Cultivadas , Decídua/citologia , Matriz Extracelular/genética , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/fisiopatologia , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/imunologia , Macrófagos/metabolismo , Músculo Liso/crescimento & desenvolvimento , Músculo Liso/imunologia , Músculo Liso/metabolismo , Gravidez , Primeiro Trimestre da Gravidez/imunologia , Alicerces Teciduais , Transcrição Gênica/imunologia , Útero/crescimento & desenvolvimento , Útero/imunologia , Útero/metabolismo
8.
bioRxiv ; 2023 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-37214839

RESUMO

Embryogenesis requires coordinated gene regulatory activities early on that establish the trajectory of subsequent development, during a period called the maternal-to-zygotic transition (MZT). The MZT comprises transcriptional activation of the embryonic genome and post-transcriptional regulation of egg-inherited maternal mRNA. Investigation into the MZT in animals has focused almost exclusively on bilaterians, which include all classical models such as flies, worms, sea urchin, and vertebrates, thus limiting our capacity to understand the gene regulatory paradigms uniting the MZT across all animals. Here, we elucidate the MZT of a non-bilaterian, the cnidarian Hydractinia symbiolongicarpus . Using parallel poly(A)-selected and non poly(A)-dependent RNA-seq approaches, we find that the Hydractinia MZT is composed of regulatory activities analogous to many bilaterians, including cytoplasmic readenylation of maternally contributed mRNA, delayed genome activation, and separate phases of maternal mRNA deadenylation and degradation that likely depend on both maternally and zygotically encoded clearance factors, including microRNAs. But we also observe massive upregulation of histone genes and an expanded repertoire of predicted H4K20 methyltransferases, aspects thus far unique to the Hydractinia MZT and potentially underlying a novel mode of early embryonic chromatin regulation. Thus, similar regulatory strategies with taxon-specific elaboration underlie the MZT in both bilaterian and non-bilaterian embryos, providing insight into how an essential developmental transition may have arisen in ancestral animals.

9.
Evodevo ; 14(1): 13, 2023 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-37620964

RESUMO

The second annual Cnidarian Model Systems Meeting, aka "Cnidofest", took place in Davis, California from 7 to 10th of September, 2022. The meeting brought together scientists using cnidarians to study molecular and cellular biology, development and regeneration, evo-devo, neurobiology, symbiosis, physiology, and comparative genomics. The diversity of topics and species represented in presentations highlighted the importance and versatility of cnidarians in addressing a wide variety of biological questions. In keeping with the spirit of the first meeting (and its predecessor, Hydroidfest), almost 75% of oral presentations were given by early career researchers (i.e., graduate students and postdocs). In this review, we present research highlights from the meeting.

10.
Proc Natl Acad Sci U S A ; 106(14): 5767-72, 2009 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-19304799

RESUMO

Human decidual CD14(+) macrophages and CD56(+) NK cells were isolated from material obtained after first-trimester pregnancy terminations. Each cell type expressed a specific surface receptor for histocompatibility leukocyte antigen (HLA)-G (an MHC class Ib protein that is expressed on extravillous trophoblasts), LILRB1 on CD14(+) macrophages and KIR2DL4 on CD56(+) NK cells. Cross-linking with anti-LILRB1 or anti-KIR2DL4 resulted in up-regulation of a small subset of mRNAs including those for IL-6, IL-8, and TNFalpha detected using a microarray representing 114 cytokines. Incubation with transfectants expressing the HLA-G homodimer (but not with transfectants expressing the HLA-G monomer) resulted in secretion of the same cytokine proteins from both leukocyte sets. Moreover, cytokine secretion from both leukocyte sets was blocked by both the appropriate anti-receptor mAb and by anti-HLA-G. The amount of these cytokines secreted by decidual macrophages was substantially greater than that secreted by decidual NK cells. VEGF was constitutively secreted by both cell types. LILRB1, which contains an immunoreceptor tyrosine-based switch motif, functions here as an activating receptor, although it has been known as an inhibitory receptor. KIR2DL4 also functions as an activating receptor, although it also has the potential to function as an inhibitory receptor. Secretion of proinflammatory and proangiogenic proteins supports a role for these leukocytes in important processes that are essential for successful pregnancy, but they may represent only a portion of the proteins that are secreted.


Assuntos
Citocinas/metabolismo , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Macrófagos/imunologia , Receptores Imunológicos/imunologia , Proteínas Angiogênicas/genética , Citocinas/biossíntese , Decídua/citologia , Feminino , Antígenos HLA-G , Humanos , Mediadores da Inflamação , Gravidez , Receptores KIR2DL5 , Regulação para Cima/genética , Fator A de Crescimento do Endotélio Vascular/genética
11.
Methods Mol Biol ; 2421: 91-102, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34870813

RESUMO

Many proteins expressed on the cellular surface provide signaling and cell adhesion properties required for vital cellular functions. These binding interactions can occur between different but complementary proteins such as a ligand and receptor, or between the same protein acting as both ligand and receptor. The cell aggregation assay is a straightforward technique to identify homophilic interactions from such proteins. Here we describe the procedure for testing proteins via cell aggregation assays in HEK293T cells.


Assuntos
Agregação Celular , Adesão Celular , Células HEK293 , Humanos , Ligantes , Proteínas de Membrana
12.
Animals (Basel) ; 12(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36230277

RESUMO

Hydractinia symbiolongicarpus is an emerging model organism in which cutting-edge genomic tools and resources are being developed for use in a growing number of research fields. One limitation of this model system is the lack of long-term storage for genetic resources. The goal of this study was to establish a generalizable cryopreservation approach for Hydractinia that would support future repository development for other cnidarian species. Specific objectives were to: (1) characterize basic parameters related to sperm quality; (2) develop a generalizable approach for sperm collection; (3) assess the feasibility of in vitro fertilization (IVF) with sperm after refrigerated storage; (4) assess the feasibility of IVF with sperm cryopreserved with various sperm concentrations; (5) evaluate feasibility of cryopreservation with various freezing conditions, and (6) explore the feasibility of cryopreservation by use of a 3-D printed open-hardware (CryoKit) device. Animal husbandry and sperm collection were facilitated by use of 3-D printed open hardware. Hydractinia sperm at a concentration of 2 × 107 cells/mL stored at 4 °C for 6 d were able to achieve 50% fertilization rate. It appeared that relatively higher sperm concentration (>5 × 107 cells/mL) for cryopreservation could promote fertilization. A fertilization rate of 41−69% was observed using sperm equilibrated with 5, 10, or 15% (v/v) cryoprotectant (dimethyl sulfoxide or methanol) for 20 min, cooled at a rate of 5, 10, or 20 °C/min from 4 °C to −80 °C, at a cell concentration of 108/mL, in 0.25 mL French straws. Samples cryopreserved with the CryoKit produced a fertilization rate of 72−82%. Establishing repository capabilities for the Hydractinia research community will be essential for future development, maintenance, protection, and distribution of genetic resources. More broadly, these generalizable approaches can be used as a model to develop germplasm repositories for other cnidarian species.

13.
iScience ; 24(7): 102811, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34296075

RESUMO

Many organisms use genetic self-recognition systems to distinguish themselves from conspecifics. In the cnidarian, Hydractinia symbiolongicarpus, self-recognition is partially controlled by allorecognition 2 (Alr2). Alr2 encodes a highly polymorphic transmembrane protein that discriminates self from nonself by binding in trans to other Alr2 proteins with identical or similar sequences. Here, we focused on the N-terminal domain of Alr2, which can determine its binding specificity. We pair ancestral sequence reconstruction and experimental assays to show that amino acid substitutions can create sequences with novel binding specificities either directly (via one mutation) or via sequential mutations and intermediates with relaxed specificities. We also show that one side of the domain has experienced positive selection and likely forms the binding interface. Our results provide direct evidence that point mutations can generate Alr2 proteins with novel binding specificities. This provides a plausible mechanism for the generation and maintenance of functional variation in nature.

14.
Evodevo ; 11: 7, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226598

RESUMO

Hydractinia, a genus of colonial marine cnidarians, has been used as a model organism for developmental biology and comparative immunology for over a century. It was this animal where stem cells and germ cells were first studied. However, protocols for efficient genetic engineering have only recently been established by a small but interactive community of researchers. The animal grows well in the lab, spawns daily, and its relatively short life cycle allows genetic studies. The availability of genomic tools and resources opens further opportunities for research using this animal. Its accessibility to experimental manipulation, growth- and cellular-plasticity, regenerative ability, and resistance to aging and cancer place Hydractinia as an emerging model for research in many biological and environmental disciplines.

15.
Science ; 368(6495): 1122-1127, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32381589

RESUMO

Immunological memory specific to previously encountered antigens is a cardinal feature of adaptive lymphoid cells. However, it is unknown whether innate myeloid cells retain memory of prior antigenic stimulation and respond to it more vigorously on subsequent encounters. In this work, we show that murine monocytes and macrophages acquire memory specific to major histocompatibility complex I (MHC-I) antigens, and we identify A-type paired immunoglobulin-like receptors (PIR-As) as the MHC-I receptors necessary for the memory response. We demonstrate that deleting PIR-A in the recipient or blocking PIR-A binding to donor MHC-I molecules blocks memory and attenuates kidney and heart allograft rejection. Thus, innate myeloid cells acquire alloantigen-specific memory that can be targeted to improve transplant outcomes.


Assuntos
Rejeição de Enxerto/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Inata , Memória Imunológica , Macrófagos/imunologia , Monócitos/imunologia , Receptores Imunológicos/fisiologia , Animais , Deleção de Genes , Rejeição de Enxerto/genética , Transplante de Coração , Transplante de Rim , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Receptores Imunológicos/genética
16.
Curr Biol ; 29(11): R463-R467, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163159

RESUMO

Most colonial marine invertebrates live as surface encrustations in benthic environments. As they grow, these animals frequently encounter other members of their own species. These encounters typically lead to conflict, in which the colonies aggressively compete for space, or co-existence, in which the colonies peacefully border each other. Sometimes, however, interacting colonies will engage in a form of cooperation in which they fuse together and actively share resources.


Assuntos
Invertebrados/fisiologia , Animais , Comportamento Cooperativo , Invertebrados/crescimento & desenvolvimento
17.
Evodevo ; 10: 20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508195

RESUMO

The 2018 Cnidarian Model Systems Meeting (Cnidofest) was held September 6-9th at the University of Florida Whitney Laboratory for Marine Bioscience in St. Augustine, FL. Cnidofest 2018, which built upon the momentum of Hydroidfest 2016, brought together research communities working on a broad spectrum of cnidarian organisms from North America and around the world. Meeting talks covered diverse aspects of cnidarian biology, with sessions focused on genomics, development, neurobiology, immunology, symbiosis, ecology, and evolution. In addition to interesting biology, Cnidofest also emphasized the advancement of modern research techniques. Invited technology speakers showcased the power of microfluidics and single-cell transcriptomics and demonstrated their application in cnidarian models. In this report, we provide an overview of the exciting research that was presented at the meeting and discuss opportunities for future research.

18.
Genetics ; 177(4): 2101-7, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17947438

RESUMO

The allorecognition complex of Hydractinia symbiolongicarpus is a chromosomal interval containing two loci, alr1 and alr2, that controls fusion between genetically distinct colonies. Recombination between these two loci has been associated with a heterogeneous class of phenotypes called transitory fusion. A large-scale backcross was performed to generate a population of colonies (N = 106) with recombination breakpoints within the allorecognition complex. Two distinct forms of transitory fusion were correlated with reciprocal recombination products, suggesting that alr1 and alr2 contributed differentially to the allorecognition response. Specifically, type I transitory fusion is associated with rapid and persistent separation of allogeneic tissues, whereas type II transitory fusion generates a patchwork of continuously fusing and separating tissues.


Assuntos
Hidrozoários/genética , Recombinação Genética , Animais , Sequência de Bases , Mapeamento Cromossômico , Cromossomos , Endogamia , Dados de Sequência Molecular , Fenótipo , Polimorfismo de Nucleotídeo Único
19.
Elife ; 62017 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-28574337

RESUMO

Unexpected findings from the immune system of sea urchin larvae potentially provide insights into immune signaling in ancestral animals.


Assuntos
Strongylocentrotus purpuratus , Vibrio , Animais , Epitélio , Larva , Ouriços-do-Mar
20.
Sci Immunol ; 2(12)2017 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-28783664

RESUMO

Mice devoid of T, B, and natural killer (NK) cells distinguish between self and allogeneic nonself despite the absence of an adaptive immune system. When challenged with an allograft, they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce interleukin-12 and present antigen to T cells. However, the molecular mechanisms by which the innate immune system detects allogeneic nonself to generate these DCs are not known. To address this question, we studied the innate response of Rag2-/- γc-/- mice, which lack T, B, and NK cells, to grafts from allogeneic donors. By positional cloning, we identified that donor polymorphism in the gene encoding signal regulatory protein α (SIRPα) is a key modulator of the recipient's innate allorecognition response. Donors that differed from the recipient in one or both Sirpa alleles elicited an innate alloresponse. The response was mediated by binding of donor SIRPα to recipient CD47 and was modulated by the strength of the SIRPα-CD47 interaction. Therefore, sensing SIRPα polymorphism by CD47 provides a molecular mechanism by which the innate immune system distinguishes between self and allogeneic nonself independently of T, B, and NK cells.

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