A Lineage-Specific Requirement for YY1 Polycomb Group Protein Function in Early T Cell Development

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Anna Luiza Facchetti Vinhaes Assumpcao ◽  
Guoping Fu ◽  
Zhanping Lu ◽  
Ashley Kuehnl ◽  
Renren Wen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Notch Signaling ◽  
Cell Survival ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Polycomb Group ◽  
Polycomb Group Protein

T cell development originates from hematopoietic stem and progenitor cells in the bone marrow, which migrate to the thymus and obtain T cell identification. Transcription factors play critical roles in regulating early T cell development. While Notch signals are critically required at the early stage of T cell development, the completion of T cell lineage commitment is far from the initial response to Notch signaling. Other transcription factors such as PU.1, Ikaros, and RUNX1 are required to enable progenitor cells to committee T cell lineage before Notch signaling. YY1 is a ubiquitous transcription factor and mammalian Polycomb Group Protein (PcG) with important functions to regulate lymphocytes development, stem cell self-renewal, cell proliferation, and survival. Previous study showed that YY1 can interact with the Notch1 receptor intracellular domain and regulate Notch1 transactivation activities in vitro. Thus, YY1 may also belong to the core T cell lineage regulatory factors and is required for progenitor cell commitment to T cell development. To test how loss-of-function of YY1 impacts early T cell development, we utilized a conditional Yy1 knockout allele Yy1f/f with loxP sites flanking the Yy1 promoter region and exon 1. Yy1f/fmice were crossed to the inducible Mx1-Cre. In Yy1f/fMx1-Cre mice, YY1 deletion was achieved after treatment with the pI-pC. Yy1-/- mice had significantly reduced numbers of lymphoid-primed multipotent progenitor, (LMPP), common lymphoid progenitor (CLP), and double-negative (DN) T cells compared to Yy1+/+ mice. YY1 deficiency resulted in an early T cell developmental blockage at the DN1 stage. In addition, Notch1 mRNA and protein expressions were significantly reduced in Yy1-/- thymocytes compared to Yy1+/+ thymocytes. In Yy1-/- thymocytes, Notch target gene Hes1 was also downregulated. Thus, YY1 is required for early T cell development and Notch1 signaling. YY1 mediates stable PcG-dependent transcriptional repression via recruitment of PcG proteins that catalyze histone modifications. Our previous results demonstrated that YY1 PcG function is required for Igκ chain rearrangement in early B cell development, however, it is not required for YY1 functions in promoting HSC self-renewal and maintaining HSC quiescence. Many questions remain unanswered regarding how cell- and tissue-specificity is achieved by PcG proteins. Herein, we utilized a YY1 REPO domain mutant (YY1ΔREPO). The small 25 amino acid REPO domain is necessary and sufficient for recruiting other PcG proteins to YY1-bound chromatin sites in Drosophila. While YY1ΔREPO is competent for DNA binding, transcriptional activation, transient transcriptional repression, and interaction with transcriptional coregulators such as HDACs, it is defective in all YY1 PcG functions and unable to recruit other PcG proteins to DNA. This mutant is therefore a powerful tool for dissecting mechanisms governing YY1 PcG-dependent versus -independent functions. Bone marrow cells from Yy1f/f Mx1-Cre mice were transduced retrovirally with MigR1-FlagYY1, MigR1-FlagYY1ΔREPO or MigR1 vector and transplanted into lethally irradiated CD45.1+ mice. In addition, Mx1-Cre bone marrow cells infected with MigR1 vector were used as the wild-type control and transplanted into CD45.1+ mice. While YY1 is required for DN1 to DN2 transition, YY1 PcG function/REPO domain is not required for DN1 transition. Instead, in mice lack of YY1 PcG function/REPO domain, early T cells had increased cell apoptosis and failed to survive. Interestingly, although YY1 PcG function/REPO domain is critical for early T cell survival, it is not required for YY1 regulation of Notch1 expression. We concluded that YY1 is a critical regulator for early T cell development and Notch signaling. There is a lineage-specific requirement for the YY1 PcG function/REPO domain for early T cell development. While YY1 PcG function is required for early T cell survival, it is not required for YY1 regulation of Notch1 expression. YY1 PcG and non-PcG functions promotes T cell development by unique mechanisms of promoting cell survival and Notch1 expression respectively. Disclosures No relevant conflicts of interest to declare.

scholarly journals A lineage-specific requirement for YY1 Polycomb Group protein function in early T cell development

Development ◽  
2021 ◽  
Vol 148 (7) ◽  
Author(s):  
Anna L. F. V. Assumpção ◽  
Guoping Fu ◽  
Deependra K. Singh ◽  
Zhanping Lu ◽  
Ashley M. Kuehnl ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Function ◽  
Transcriptional Repression ◽  
T Cell Development ◽  
Cell Development ◽  
Polycomb Group ◽  
Conditional Knockout ◽  
Specific Requirement ◽  
Polycomb Group Protein ◽  
Group Protein

ABSTRACT Yin Yang 1 (YY1) is a ubiquitous transcription factor and mammalian Polycomb Group protein (PcG) with important functions for regulating lymphocyte development and stem cell self-renewal. YY1 mediates stable PcG-dependent transcriptional repression via recruitment of PcG proteins that result in histone modifications. Many questions remain unanswered regarding how cell- and tissue-specificity is achieved by PcG proteins. Here, we demonstrate that a conditional knockout of Yy1 in the hematopoietic system results in an early T cell developmental blockage at the double negative (DN) 1 stage with reduced Notch1 signaling. There is a lineage-specific requirement for YY1 PcG function. YY1 PcG domain is required for T and B cell development but not necessary for myeloid cells. YY1 functions in early T cell development are multicomponent and involve both PcG-dependent and -independent regulations. Although YY1 promotes early T cell survival through its PcG function, its function to promote the DN1-to-DN2 transition and Notch1 expression and signaling is independent of its PcG function. Our results reveal how a ubiquitously expressed PcG protein mediates lineage-specific and context-specific functions to control early T cell development.

IL-7 Effects on Thymocyte Progenitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3318-3318
Author(s):  
Nahed El Kassar ◽  
Baishakhi Choudhury ◽  
Francis Flomerfelt ◽  
Philip J. Lucas ◽  
Veena Kapoor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cell ◽  
Notch Signaling ◽  
Stromal Cells ◽  
T Cell Development ◽  
Fold Increase ◽  
Cell Development ◽  
B Cell Development ◽  
Over Expression

Abstract IL-7 is a non-redundant cytokine in T cell development. We studied the role of IL-7 in early T-cell development using a model of transgenic (Tg) mice with the murine IL-7 gene under control of the lck proximal promoter. At high IL-7 over-expression (x39 fold increase at day 1 in total thymic tissue), we observed a disruption of TCRαβ development along with increased B cell development in the thymus (7- to 13-fold increase) (El Kassar, Blood, 2004). In order to further explore abnormal T and B cell thymic development in these mice, we first confirmed that they both arise in parallel and were non-cell autonomous, by in vivo injection of neutralizing anti-IL-7 MAb and mixed bone marrow chimera experiments. Using a six color flow cytometry analysis, we found a dramatic decrease of the early thymocyte progenitors (ETPs, lin−CD44+CD25−c-kithiIL-7R−/lo) in the adult Tg mice (x4.7 fold decrease). Lin−CD44+CD25−c-kit+ thymocytes were sorted and cultured on OP9 and OP9 delta-like1 (OP9-DL1) stromal cells (kindly provided by Pr Zuniga Pflucker). At day 14, we observed an important decrease of T cell development (54% vs. 1% of DP cells) and an increase of NK cells (x5 fold increase) in the Tg-derived DN1 cell culture. DN2 (Lin−CD44+CD25−c-kit+) Tg thymocytes showed the same, but less dramatic abnormalities. While DN1 progenitors developed effectively into B220+CD19+ cells on OP9 stromal cells, no B cell development was observed on OP-DL stromal cells from DN1-Tg derived progenitors or by addition of increasingly high doses of IL-7 (x10, x40, x160) to normal B6-derived DN1 progenitors. Instead, a block of T-cell development was observed with increased IL-7. We hypothesized a down regulation of Notch signaling by IL-7 over-expression and analyzed by FACS Notch expression in the DN thymocytes. By staining the intra-cellular part of Notch cleaved after Notch 1/Notch ligand activation, Tg-derived DN2 cells showed decreased Notch signaling. More importantly, HES expression was decreased in the DN2, DN3 and DN4 fractions by semi-quantitative PCR. Sorted Pro/Pre B cells from Tg thymi showed TCR Dβ1-Jβ1 rearrangement indicating their T specific origin, in opposition to Pro/Pre B cells sorted from the bone marrow of the same mice. We suggest that more than one immature progenitor seeds the thymus from the bone marrow. While ETPs had T and NK proliferative capacity, another thymic progenitor with B potential may be responsible for thymic B cell development in normal and IL-7 Tg mice. Finally, IL-7 over-expression may induce a decreased Notch signaling in thymic progenitors, inducing a switch of T vs. B lineage development.

T and B cell development in pituitary deficient insulin-like growth factor-II transgenic dwarf mice

1997 ◽  
Vol 155 (1) ◽  
pp. 165-170 ◽  
Author(s):  
R Kooijman ◽  
SC van Buul-Offers ◽  
LE Scholtens ◽  
RG Reijnen-Gresnigt ◽  
BJ Zegers
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Development ◽  
B Cell Development ◽  
Igf I ◽  
Dwarf Mice

Treatment of mice with IGF-I stimulates T and B cell development. We showed that overexpression of IGF-II in transgenic FVB/N mice only stimulated T cell development. In the present study, we further addressed the in vivo effects of IGF-II in the absence of IGF-I to get more insight into the potential abilities of IGF-II to influence T and B cell development. To this end, we studied lymphocyte development in IGF-II transgenic Snell dwarf mice that are prolactin, GH and thyroid-stimulating hormone deficient and as a consequence show low serum IGF-I levels. We showed that T cell development was stimulated to the same extent as in IGF-II transgenic FVB/N mice. Furthermore, IGF-II increased the number of nucleated bone marrow cells and the number of immature B cells without having an effect on the number of mature B cells in spleen and bone marrow. Our data show that IGF-II has preferential effects on T cell development compared with B development, and that these preferential effects also occur in the absence of measurable IGF-I levels.

Loss of FLVCR, a Heme Export Protein, Blocks Thymic T Cell Development at the CD4+CD8+ Double-Positive Stage.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 913-913
Author(s):  
Mary Philip ◽  
Jing Chen ◽  
Raymond T Doty ◽  
Janis L. Abkowitz
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Development ◽  
Feline Leukemia Virus ◽  
Intrinsic Defect ◽  
Double Positive ◽  
Rag 1

Abstract Abstract 913 Cats viremic with the feline leukemia virus C (FeLV-C) develop profound anemia with an early block in erythroid development. In infected cells, the FeLV-C envelope protein sequesters its receptor, feline leukemia virus subgroup Creceptor (FLVCR), in the endosomal compartment and prevents FLVCR trafficking to the cell surface. FLVCR is a transmembrane protein and major facilitator superfamily member, which we previously showed exports heme from cells [Cell(2004)118:57]. FLVCR-null mice died in utero with failed definitive erythropoiesis [Science(2008)319:825]. Conditionally-deleted mice (Flvcrflox/flox;Mx-cre) were then generated, and neonatal or adult deletion caused progressive anemia similar to that seen in cats infected with FeLV-C. In addition to its role as an oxygen carrier in hemoglobin, heme has many other important and diverse roles, including regulation of several transcription and translation factors, microRNA processing, and N-end rule ubiquitination. Early reports noted that cats viremic with FeLV-C had thymic aplasia and lymphopenia. However, it was unclear whether these findings were due to a thymus-intrinsic defect, or a secondary effect of severe anemia and resultant stress. In order to study the role of FLVCR in lymphocyte development, we transplanted limiting numbers (2 × 106) of FLVCR-deleted (FLVCR KO) or control (FLVCR +/+ or +/flox;Mx-cre littermate) bone marrow cells into sub-lethally irradiated (500 cGy) Rag 1-deficient (Rag1 KO) mice. Rag 1KO mice cannot recombine T cell receptor (TCR) or immunoglobulin genes and have no T or B cells. The use of sub-lethal irradiation and transplantation of low numbers of FLVCR KO bone marrow cells allowed endogenous Rag1KO hematopoietic cells to contribute to the erythroid lineage, preventing anemia. However, any T or B cells that developed had to arise from the transplanted FLVCR KO bone marrow. As expected, the FLVCR KO-transplanted Rag1 KO mice were not anemic. However, very few T cells were found in the peripheral blood, spleen, or lymph nodes of FLVCR KO-transplanted mice compared to controls (>90% reduction). In contrast, B cell numbers were preserved. Thus, the previously observed thymic aplasia and lymphopenia seen in FeLV-C viremic cats was not due to severe anemia or stress, but to a direct effect of FLVCR loss on T cell development. Since thymic epithelial cells and the majority of myeloid cells were derived from the Rag1 KO host, the block in T cell development was caused by a cell-intrinsic defect in developing FLVCR KO thymocytes. The requirement for FLVCR was at a developmental stage downstream of the common lymphoid progenitor because B cells developed normally. We then analyzed thymic development in Rag 1 KO mice transplanted with FLVCR KO or control bone marrow. While there were similar numbers of CD4-CD8- double-negative thymocytes (DN) and a slight diminution in the number of CD4+CD8+ double-positive thymocytes (DP), there was a dramatic decrease in the number of CD4+ and CD8+ single positive thymocytes (SP) in FLVCR KO-transplanted mice compared to controls (82% reduction). Analysis of surface TCR expression as well as other maturation markers on developing thymocytes showed that TCR beta rearrangement occurred in FLVCR KO-transplanted mice. However, there was progressive loss of FLVCR KO-derived thymocytes at each subsequent stage. Thus, FLVCR is required for T cell development beyond the DP stage. Following TCR beta rearrangement and surface expression, thymocytes proliferate extensively, rearrange TCR alpha genes, and then undergo positive and negative selection. Our findings suggest that excessive heme caused by FLVCR loss impairs T cell development during these stages, and are intriguing because thus far, heme has not been shown to play a role in T cell development. Whether direct heme toxicity impairs thymocyte proliferation and/or induces apoptosis, or whether excessive heme derails the T cell developmental transcriptional/translational programs, remains to be discovered. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Functional definition of a transcription factor hierarchy regulating T cell lineage commitment

2020 ◽  
Vol 6 (31) ◽  
pp. eaaw7313 ◽  
Author(s):  
Laura Garcia-Perez ◽  
Farbod Famili ◽  
Martijn Cordes ◽  
Martijn Brugman ◽  
Marja van Eggermond ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Notch Signaling ◽  
Target Genes ◽  
T Cell Development ◽  
Cell Lineage ◽  
Specific Protein ◽  
Cell Development

T cell factor 1 (Tcf1) is the first T cell–specific protein induced by Notch signaling in the thymus, leading to the activation of two major target genes, Gata3 and Bcl11b. Tcf1 deficiency results in partial arrests in T cell development, high apoptosis, and increased development of B and myeloid cells. Phenotypically, seemingly fully T cell–committed thymocytes with Tcf1 deficiency have promiscuous gene expression and an altered epigenetic profile and can dedifferentiate into more immature thymocytes and non-T cells. Restoring Bcl11b expression in Tcf1-deficient cells rescues T cell development but does not strongly suppress the development of non-T cells; in contrast, expressing Gata3 suppresses their development but does not rescue T cell development. Thus, T cell development is controlled by a minimal transcription factor network involving Notch signaling, Tcf1, and the subsequent division of labor between Bcl11b and Gata3, thereby ensuring a properly regulated T cell gene expression program.

T Cell Acute Lymphoblastic Leukemia Originates from a Differentiation Block in T Cell Development Due to Aberrant Expression of LMO2 and SCL(TAL1).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2215-2215
Author(s):  
Gerlinde Layh-Schmitt ◽  
Scott Crable ◽  
Kathleen Crable ◽  
Elizabeth Kraft ◽  
Jeff Bailey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Development ◽  
Aberrant Expression ◽  
Differentiation Block ◽  
Marrow Cells

Abstract T cell acute lymphoblastic leukemia (T-ALL) is frequently associated with overexpression of the oncogenes LMO2 and SCL(TAL1) which are normally down regulated following the double negative stage of T cell development. Our goal is to decipher the molecular and cellular mechanisms leading to the onset of LMO2 associated T-ALL. We were able to isolate a complex containing the transcription factors LMO2, SCL(TAL1) and E47 from primary human T-ALL cells with proven aberrant expression of LMO2 and SCL(TAL1) by applying immunoprecipitation and Western blotting techniques. This protein complex regulates the transcription of a truncated form of RALDH2 (retinaldehyde dehydrogenase) in T-ALL cells as shown by gene transcription profiling in conjunction with RT-PCR and siRNA approaches. To monitor the effect of LMO2 expression on T cell development and leukemogenesis, lethally irradiated mice (C57BL/6) were transplanted with bone marrow cells that had been transduced with a retrovirus carrying LMO2 as the transgene. One year later, 88% of the cells in the thymus expressed LMO2 and a shift towards CD3−/CD44+/CD25+ cells was observed (an 88% increase compared to normal thymocytes), suggesting a differentiation block caused by LMO2 leading to an accumulation of immature T cells. To test and identify cooperating genes in T-ALL development, bone marrow cells of LMO2 double transgenic mice in which tet-inducible LMO2 is controlled by a thymic specific promoter, were retrovirally transduced with SCL(TAL1). So far, none of the control animals, transplanted with bone marrow cells transduced with a vector only containing EGFP, developed T-ALL. However, six out of the seven test animals developed T-ALL exhibiting enlargement of the spleen, liver and thymus between seven and nine months after transplantation. Organs and blood of the diseased animals were infiltrated with T-ALL cells of the immature phenotype CD8+/CD4+ in five cases and of the CD3−/CD44+/CD25+ phenotype in one case. This indicates that the differentiation block caused by a lack of down-regulation of LMO2 and SCL(TAL1) in maturing T cells leads to a block in T cell differentiation and precedes T-ALL. These models will be used to examine the involvement of other cooperating genes in T-ALL development as well as downstream target genes of LMO2/SCL(TAL1), such as RALDH2, in the onset of T-ALL. We conclude that aberrant expression of LMO2 in T cells leads to a block in T cell maturation and, in conjunction with up-regulation of secondary genes like SCL(TAL1), triggers deregulation of genes in immature T cells leading to impaired T cell development and the onset of T-ALL. The described model will help to identify cooperating genes in LMO2 associated T-ALL as well as the chain of events leading to malignancy.

T/B lineage choice occurs prior to intrathymic Notch signaling

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 886-892 ◽  
Author(s):  
Benjamin C. Harman ◽  
William E. Jenkinson ◽  
Sonia M. Parnell ◽  
Simona W. Rossi ◽  
Eric J. Jenkinson ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Notch Signaling ◽  
Fetal Liver ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Fetal Mouse ◽  
Mouse Thymus ◽  
B Lineage

Abstract Commitment of hemopoietic progenitors to the T-cell lineage is a crucial requirement for T-cell development, yet the timing and developmental cues regulating this process remain controversial. Here we have devised a technique to analyze the T-cell/B-cell lineage potential of precursors that have been recruited to the fetal mouse thymus but which have yet to contact the thymic epithelial microenvironment. We show that lymphoid progenitors arriving at the thymus are not bipotent T/B precursors, and provide evidence that intrathymic Notch signaling is not the mechanism determining T/B lineage choice in migrant precursors. Rather, we provide evidence that Notch signaling influences T/B lineage choice in lymphoid precursors through interactions with defined stromal components within the fetal liver. Collectively, our data redefine our understanding of the role and timing of Notch signaling in relation to lineage choices in lymphoid precursors.

Mouse CD11c+ B220+ Gr1+plasmacytoid dendritic cells develop independently of the T-cell lineage

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2852-2857 ◽  
Author(s):  
Isabel Ferrero ◽  
Werner Held ◽  
Anne Wilson ◽  
Fabienne Tacchini-Cottier ◽  
Freddy Radtke ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Lineage ◽  
Notch 1 ◽  
T Cell Factor ◽  
Plasmacytoid Dcs ◽  
Lineage Markers ◽  
Mixed Chimeras

The developmental origin of dendritic cells (DCs) is controversial. In the mouse CD8α+ and CD8α− DC subsets are often considered to be of lymphoid and myeloid origin respectively, although evidence on this point is conflicting. Very recently a novel CD11c+ B220+ DC subset has been identified that appears to be the murine counterpart to interferon alpha (IFNα)–producing human plasmacytoid DCs (PDCs). We show here that CD11c+ B220+ mouse PDCs, like human PDCs, are present in the thymus and express T lineage markers such as CD8α and CD4. However, the intrathymic development of PDCs can be completely dissociated from immature T lineage cells in mixed chimeras established with bone marrow cells from mice deficient for either Notch-1 or T-cell factor 1, two independent mutations that severely block early T-cell development. Our data indicate that thymic PDCs do not arise from a bipotential T/DC precursor.

scholarly journals Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2453-2460 ◽  
Author(s):  
Önder Alpdogan ◽  
Vanessa M. Hubbard ◽  
Odette M. Smith ◽  
Neel Patel ◽  
Sydney Lu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Growth Factor ◽  
Keratinocyte Growth Factor ◽  
Critical Role ◽  
T Cell Development ◽  
Marrow Transplant ◽  
Cell Development ◽  
Allogeneic Bone ◽  
Thymic Regeneration

AbstractKeratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that mediates epithelial cell proliferation and differentiation in a variety of tissues, including the thymus. We studied the role of KGF in T-cell development with KGF-/- mice and demonstrated that thymic cellularity and the distribution of thymocyte subsets among KGF-/-, wildtype (WT), and KGF+/- mice were similar. However, KGF-/- mice are more vulnerable to sublethal irradiation (450 cGy), and a significant decrease was found in thymic cellularity after irradiation. Defective thymopoiesis and peripheral T-cell reconstitution were found in KGF-/- recipients of syngeneic or allogeneic bone marrow transplant, but using KGF-/- mice as a donor did not affect T-cell development after transplantation. Despite causing an early developmental block in the thymus, administration of KGF to young and old mice enhanced thymopoiesis. Exogenous KGF also accelerated thymic recovery after irradiation, cyclophosphamide, and dexamethasone treatment. Finally, we found that administering KGF before bone marrow transplantation (BMT) resulted in enhanced thymopoiesis and peripheral T-cell numbers in middle-aged recipients of an allogeneic BM transplant. We conclude that KGF plays a critical role in postnatal thymic regeneration and may be useful in treating immune deficiency conditions. (Blood. 2006;107:2453-2460)

Sign in / Sign up

Export Citation Format

Share Document