CD95L was upregulated in HIV-infected APCs, and led to suppressed T cell activation. 1995 Feb 15;154(4):1675-83. Malcovati Davis When analyzing a CD71+ neoplastic process of uncertain lineage involving the bone marrow, confirmation of erythroid lineage using additional markers such as CD235a and hemoglobin is advised. CD71 (transferrin receptor) is an activation marker and can be expressed on different immune cells including T cells . The vast majority of mature erythrocytes were negative for CD71, greatly facilitating interpretation. Residual erythroid precursors are CD71+ and demonstrate variation in staining intensity, with strongest immunoreactivity noted for early erythroid precursors and more delicate membranous reactivity for the late erythroid (left and right, immunoperoxidase, ×600). In cases of MDS, AML, plasma cell neoplasm, and metastatic carcinoma Image 2, CD71 served as the most effective marker for the detection of admixed erythroid precursors owing to their distinct staining pattern and lack of reactivity in mature erythrocytes. Depending on the duration of acti-vation response after the stimulus, CD markers can be divided into early stimulation (CD69+ and CD71 +) and late activation (CD25 , … Sargent Della Porta This study was approved by the Brigham and Women’s Hospital Institutional Review Board. However, for many markers (eg, CD235a, hemoglobin, myeloperoxidase, lysozyme, cytoplasmic immunoglobulin light and heavy chains, and CD138), excellent immunohistochemical results may be achieved without antigen retrieval. Sections were counterstained with hematoxylin, dehydrated, and mounted. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. JN Cao et al. et al. The results of immunohistochemical studies for CD71, CD235a, and hemoglobin are summarized in Table 1. For T cell activation to take place, in addition to the TCR binding to antigen peptide presented by MHC, simultaneous binding to a co-receptor molecule is required. Detection was performed using the EnVision+ system (DAKO) with DAB+ (DAKO) as the chromogen. Surface markers studied were the activation markers CD26 (a proposed Th1 marker), CD69, CD95 (also known as Fas, ligation of which induces programmed cell death) and gp240.10 The expression of CD28 (co-stimulatory), CD54 (adhesion), and CD57 (subset marker) was also investigated. This study defined the immunohistochemical profile of CD71, as compared with glycophorin A (CD235a) and hemoglobin, in 65 bone marrow biopsy specimens, including normal marrow specimens and cases of myelodysplastic syndrome, acute myeloid leukemia, acute lymphoblastic leukemia, plasma cell neoplasm, and metastatic carcinoma. A subpopulation of cells within tumors has been suggested to possess the ability to initiate tumorigenesis and contribute to resistance to cancer therapy. M Additional regulatory mechanisms leading to CD71 activation in ESCC require further investigation. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. , eds. S This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. Understanding what these activation markers are, when they are expressed, and their role in T cell function during normal responses and disease states is important when selecting markers for assessing T cell biology for studies on human PBMC. There are a large number of commonly used macrophage markers such as CD14, CD16, CD64, CD68, CD71 and CCR5; the exact marker to be used will be dependent upon the subset of macrophage and the conditions of their local environment. 1997 Jan 1;27(1):71-6. Bene In the previous posting, I discussed two immediate early activation markers for assessing the activation status of human PBMC T cells: CD69 and CD40L. We also examined CD71 expression in 7 formalin-fixed marrow samples, including 4 cases of MDS and 3 cases of AML, to ensure that the same conditions would apply. The endometrial T cells expressed high levels of CD69 (84.1% ± 18.9%) and DR (75.9% ± 9.7%), but rarely expressed CD25 (7.0% ± 5.4%) and CD71 (2.8% ± 1.8%). Second, CD71 expression is restricted to erythroid lineage within bone marrow biopsy specimens. CD69 is a very early activation marker and is detectable within hours of TCR ligation then expression is lost after 48-72 hours. PD-L1 is an activation-induced cell marker in humans and has been successfully used in conjunction with OX40 or CD25 to identify antigen-specific cells (Fig 4E, see ). Sadahira Studies for CD71 were performed following heat-induced epitope retrieval in a steamer using Retrieve-All-2 (Covance Research Products, Dedham, MA). CD71 (transferrin receptor), a cell surface proliferation marker, is involved in the cellular uptake of iron (1-3). Compared with results for CD71, studies for CD235a and hemoglobin were weaker in early erythroblasts. B, In a case of acute pure erythroid leukemia, greater than 80% of cellularity is composed of erythroblasts, which are positive for CD71 (A and B, left, H&E, ×600; right, immunoperoxidase, ×600). Bennett Multiparametric flow cytometric analysis of the kinetics of surface molecule expression after polyclonal activation of human peripheral blood T lymphocytes. Third, expression of CD71 decreases with maturation, with the highest level seen in early forms and the lowest level in late normoblasts. S Our data show that the kinetics of expression of these activation markers follows a precise and consistent time-course with some differences between mouse and human T cells. In addition, 4 cases of MDS and 3 cases of AML that had been fixed in formalin were also examined. Visualization of PBMC activation using phase-contrast imaging and live-cell ICC (anti-CD71 Fabfluor-488). Traditional markers for erythroid lineage, such as hemoglobin and glycophorin A (also referred to as CD235a), may be difficult to interpret owing to reactivity of both markers for abundant mature nonnucleated erythrocytes in the marrow and the cytoplasmic staining pattern of hemoglobin.12 The goal of this study was to evaluate the distribution and specificity of CD71 immunoreactivity for erythroid precursors in a variety of clinical settings in paraffin-embedded bone marrow biopsy specimens, in comparison with immunohistochemical studies for hemoglobin and CD235a. email: info@sanguinebio.com, EGF enhances HSC regeneration following myelosuppressive injury, The Seven Years That Changed Everything For Everybody, Effective Logo Design: Symbols, Metaphors And The Power Of Intuition, Don’t Get Crushed By The Load: Optimization Techniques And Strategies, Think Again: Assumptions About Mobile To Reconsider, Black Sesame Cherry Rose Pie and My Trip to Maddocks Farm Organics. These erythroid precursors co-express the transferrin receptor CD71 and erythroid marker TER119 in mice, and CD71 and CD235a in humans (13, 14). Caine *Image courtesy of http://en.wikipedia.org/wiki/Fas_ligand*, 28903 Avenue Paine J Clin Invest. Compared with CD235a and hemoglobin, the stain for CD71 highlighted occasional mature erythrocytes, but the level of staining was very faint. Grandclaudon M et al used IL-12Rb2 as a T H 1 cell marker . With regard to T H 17 cells, their differentiation is under control TGF-β and IL-6-induced differentiation, IL-21-induced activation, and IL-23-regulated stabilization [15, 16]. Although an aspirate count may be preferred over immunohistochemical staining of biopsy specimens for determining the percentage of erythroid elements, immunostains on bone marrow biopsy specimens are sometimes necessary if adequate aspirate smears are not available and in cases with marked dyserythropoiesis. Lum JB, Infante AJ, Makker DM, Yang F, Bowman BH. It is the earliest and easiest to detect. Critchley-Thorne RJ, Simons DL, Yan N, Miyahira AK, Dirbas FM, Johnson DL, Swetter SM, Carlson RW, Fisher GA, Koong A, Holmes S, Lee PP. The most typical marker for T cell activation is CD69. Supplied as 100 µg purified antibody (0.2 mg/mL). Biselli R, Matricardi PM, D’Amelio R, Fattorossi A. Scand J Immunol. Accurate analysis of the erythroid lineage is essential in evaluating bone marrow biopsy specimens and can be particularly challenging in the setting of dyserythropoiesis. IS CD71 (TFRC, Transferrin Receptor, TfR) is a cell surface iron transport receptor that is upregulated in proliferating cells by 24-48 hours following T cell activation and expression continues to rise and is maintained for several days. The staining pattern for CD235a was largely membranous, and the staining pattern for hemoglobin was mainly cytoplasmic. The transferrin receptor (CD71) is an integral membrane protein that mediates the uptake of transferrin-iron complexes.1 Two transferrin receptors have been cloned (TfR1 and TfR2); however, TfR1 is considered the major protein responsible for iron uptake owing to its higher affinity and expression pattern.2 CD71 is a homodimeric glycoprotein containing 760 amino acids, and it binds to diferric transferrin at the cell surface.3 This binding is followed by internalization, a process that is regulated in part by interaction with the HFE protein, which is mutated in patients with hereditary hemochromato-sis.4 Diferric iron is subsequently released from transferrin owing to endosomal acidification. Babyonyshev 2012 Sep 8;413(17-18):1338-49. CD71 has been shown to exhibit strong membranous and cytoplasmic staining in all erythroid precursors of normal and dyspoietic bone marrow biopsies (1,2). Representative H&E-stained and Giemsa-stained sections were reviewed to confirm the diagnoses. It appears that these activated nonerythroid lineage cells in VISTA KO mice consist of different immune cells, but the majority were CD3 + T cells . The ASCP designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Invernizzi Indeed, Strauss et. In formalin-fixed bone marrow samples, the intensity, specificity, and pattern of CD71 expression were comparable to those with Zenker fixative, including an absence of reactivity for mature erythrocytes. DM The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. (A–C) Representative plots and quantification of CD71 + Ter119 + cells (A), CD4 + T cells and CD8 + T cells (B), and activation marker NKp46 in CD3 – CD49b + cells and total NK cell counts (C) in livers of RRV-infected mice pretreated with either rat IgG or anti-CD71 antibody. Owing to the lack of background staining of mature erythrocytes in the CD71 study, the erythroid precursors appear more distinct and are readily discernible. Cytomorphologic Spectrum of SMARCB1-Deficient Soft Tissue Neoplasms: About American Journal of Clinical Pathology, About the American Society for Clinical Pathology, Receive exclusive offers and updates from Oxford Academic, ALDH, CA I, and CD2AP: Novel, Diagnostically Useful Immunohistochemical Markers to Identify Erythroid Precursors in Bone Marrow Biopsy Specimens, An Immunohistochemical Study of Hemoglobin A, Hemoglobin F, Muramidase, and Transferrin in Erythroid Hyperplasia and Neoplasia, GATA1 Is a Sensitive and Specific Nuclear Marker for Erythroid and Megakaryocytic Lineages, Cyclin D1 Overexpression in Multiple Myeloma: A Morphologic, Immunohistochemical, and In Situ Hybridization Study of 71 Paraffin-Embedded Bone Marrow Biopsy Specimens, Copyright © 2021 American Society for Clinical Pathology. G SH CD71 + erythroid cells (CECs) are abundant in the spleen of neonatal mice (13–15), placenta tissues and expand during pregnancy in the peripheral blood/spleen of allogeneic mice . CD71 is a robust immunohistochemical marker for the detection of nucleated red blood cells and chorionic villi, especially in presence of necrosis (Appl Immunohistochem Mol Morphol 2016;24:215) Demonstration of nucleated red blood cells can be important in molar pathology, helping to exclude a complete mole (Appl Immunohistochem Mol Morphol 2016;24:215) Surface markers of lymphocyte activation and markers of cell proliferation. In cases of acute pure erythroid leukemia (FAB AML-M6b), reactivity for CD71 clearly demonstrated that the blasts were of erythroid lineage (Image 3B). RW In normal bone marrow samples, reactivity for CD71 was specific and restricted to erythroid lineage, with the highest intensity of membranous and cytoplasmic staining seen in early erythroid precursors and the lowest level in late normoblasts Image 1. 2009 Jun 2;106(22):9010-5. Lymphocyte activation markers may predict the presence of donor specific alloreactivity in pediatric living related liver transplant recipients. Wada Valencia, CA Studies for hemoglobin and CD235a also detected immature erythroid elements; however, interpretation was compromised by strong reactivity of the background admixed abundant mature erythrocytes. 2004 Oct;293(1-2):127-42. J First, it has a distinct membranous and cytoplasmic staining pattern, which is easily recognizable. Transferrin synthesis by inducer T lymphocytes. Kanzaki There are very few unique macrophage markers and often a number of markers will be required to identify your cell type. Roy Paulsen M, Janssen O. CD69 is a marker expressed on recently activated T cells (hours after activation), HLA-DR is expressed later (days–weeks after activation) and CD71… It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Evans The vast majority of mature erythrocytes lack expression of CD71, greatly facilitating interpretation. Reddy M, Eirikis E, Davis C, Davis HM, Prabhakar U. J Immunol Methods. CN S Pro- and anti-apoptotic CD95 signaling in T cells. Schulte The patterns of expression of these activation markers were similar in both proliferative and luteal phases. Studies for hemoglobin exhibited the highest background. et al. CD71 has been studied for use in the assessment of leukemias and myelodysplastic syndromes (MDSs) in flow cytometric studies, in which expression serves as a lineage marker for the diagnosis of erythroid leukemia.9 In addition, several studies have demonstrated that CD71 expression is decreased in dysplastic erythroid precursors.10,11 However, the usefulness of CD71 expression has not been examined in paraffin-embedded bone marrow biopsy specimens. Feder A prior study showed that spectrin is also superior to CD235a for detection of erythroid precursors.15 Spectrin was most highly expressed in early erythroid precursors (cytoplasmic), with decreasing expression in maturing forms (membranous), including mature erythrocytes. H CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling. Derek K. Marsee, MD, PhD, Geraldine S. Pinkus, MD, Hongbo Yu, MD, PhD, CD71 (Transferrin Receptor): An Effective Marker for Erythroid Precursors in Bone Marrow Biopsy Specimens, American Journal of Clinical Pathology, Volume 134, Issue 3, September 2010, Pages 429–435, https://doi.org/10.1309/AJCPCRK3MOAOJ6AT. Thus CD71 may be aberrantly expressed by T cells in human disease. Bicknell T cell activation and exhaustion are biological events in the immune system. Exam is located at www.ascp.org/ajcpcme. Strauss G, Lindquist JA, Arhel N, Felder E, Karl S, Haas TL, Fulda S, Walczak H, Kirchhoff F, Debatin KM. R Lawrence A, The CD71 staining pattern demonstrates that the majority of the cells are erythroid precursors in a case of acute erythroid/myeloid leukemia. MG CD71 was more effective than the other markers owing to highest expression in immature erythroid elements and its lack of reactivity in admixed erythrocytes (Image 3A). In paraffin-embedded tissue, particularly in dyspoietic marrow samples, erythroid precursors may not be easily differentiated from other types of precursors on H&E-stained and Giemsa-stained sections, and immunohistochemical analysis is useful for this distinction. D Flow cytometry has advanced rapidly allowing us to be able to define a detailed characterization of T cells in both states. Because mature erythrocytes express spectrin, it is most likely that immunohistochemical studies for spectrin will have high background compared with CD71. A, Normal bone marrow biopsy specimen with trilineage hematopoiesis (H&E, ×1,000). The majority of cases in the study were fixed in Zenker fixative, which is routinely used at our institution because it provides superior cytologic detail. Studies for glycophorin A and hemoglobin did not require antigen retrieval. Campo Cell Commun Signal. As was similarly discussed for CD69, Critchley-Thorne et. First, it has a distinct membranous and cytoplasmic staining pattern, which is easily recognizable. Udeme D ... CD69 and CD71 cell surface expression with interferon-γ secretion can be used to identify two distinct populations in pediatric LT recipients. Immunohistochemical studies were performed on 4-μm-thick paraffin-embedded tissue sections. et al. Salmerón A, Borroto A, Fresno M, Crumpton MJ, Ley SC, Alarcón B. J Immunol. Like CD71, CD95 expression can be detected by 24 hours following T cell activation and continues to increase over the course of several days. et al. define the advantages of CD71 when compared to hemoglobin and CD235a. In cases of acute erythroid leukemias Image 3, CD71 was also the most sensitive marker in demonstrating the erythroid precursors and erythroblasts. Daniel Swerdlow D, Neoplastic cells also are negative for CD71 in a case of plasma cell neoplasm (left) and metastatic prostatic adenocarcinoma (right). Some authors report lack of activation markers expression (e.g., CD69 or CD71) on Tregs’ surface, but the others documented their expression on Tregs or even increased CD69 expression after specific therapy. et al. Furthermore, we identified CD71 as a marker associated with the earliest neutrophil developmental stages. In this study, we demonstrated that CD71, compared to CD235a and hemoglobin, is a highly effective marker for highlighting erythroid precursors in bone marrow biopsy specimens for several reasons. Flow cytometric analysis of activation markers on stimulated T cells and their correlation with cell proliferation. Thus, CD71 staining is a robust, specific marker for erythroid precursors in Zenker- and formalin-fixed bone marrow biopsy specimens. 1986 Mar;77(3):841-9. Bone marrow biopsy specimen in acute erythroid leukemia. However, this negative co-stimulatory effect appears to be dose-dependent, as low doses of CD95 agonists had the opposite effect and strongly promoted activation and proliferation of T cells. We found that erythroid precursor cells, co-expressing the transferrin receptor CD71 and erythroid marker TER119, are present in impressively high numbers in … et al. Following deparaffinization, mercury salts were removed from Zenker-fixed tissues and slides were treated for 5 minutes with 3% hydrogen peroxide to eliminate endogenous peroxidase activity. PBMCs (30K/well) were treated with anti-CD3 and IL-2, or vehicle control, and labeled using anti-CD71-Fabfluor-488. Paraffin sections of 58 bone marrow biopsy specimens fixed in Zenker solution were analyzed: 10 normal marrow samples, 11 cases of MDS with excess blasts (refractory anemia with excess blasts [RAEB-1 or RAEB-2]); 24 cases of AML, including 2 each of FAB subtypes M0-M5, 7 cases of acute erythroid/myeloid leukemia (FAB AML-M6a), 5 cases of acute pure erythroid leukemia (FAB AML-M6b), and 5 cases of acute lymphoblastic leukemia; 3 cases of plasma cell neoplasm; and 5 cases of metastatic carcinoma. However, the major limitation of Zenker-fixed material is that immunohistochemical studies for some markers may be difficult, requiring antigen retrieval or other technical steps, including dezenkerization. CD71 + and CD71 − AMs were phenotypically, functionally, and transcriptionally distinct, with CD71 − AMs characterized by reduced expression of markers of macrophage maturity, impaired phagocytosis, and enhanced expression of profibrotic genes. To assess cell-mediated immunity to Toxoplasma gondii , we evaluated the expression of the activation antigens CD69, CD71, and CD25 on T lymphocytes by flow cytometry after specific in vitro stimulation of whole blood from 127 T. gondii -positive and 63 T. gondii -negative patients. Farnaud However, future studies may be warranted to compare these markers of erythroid elements in paraffin sections in order to determine which is preferable. It is well known as a marker for cell proliferation and activation. . Penny et al. Identification and isolation of this subpopulation in cancer cells can be achieved by detecting specific cell-surface markers. Slides were incubated for 1 hour at room temperature with antibodies against CD71 (clone H68.4, dilution 1:1,000; Invitrogen, South San Francisco, CA), glycophorin A (CD235a, clone JC159, dilution 1:1,000; DAKO, Carpinteria, CA), and hemoglobin (rabbit polyclonal, dilution 1:3,000; DAKO). Second, CD71 expression is restricted to erythroid lineage within bone marrow biopsy specimens. Tested in Flow Cytometry (Flow) applications. Trowbridge Malcovati © American Society for Clinical Pathology, Mucinous Adenocarcinoma With Intrapulmonary Metastasis Harboring, A Tertiary Academic Medical Center Blood Bank’s Experience With Four-Factor Prothrombin Complex Concentrate. In studies for hemoglobin (D) and CD235a (C), abundant erythrocytes are positive, compromising interpretation (C and D, immunoperoxidase, ×1,000). al, 2007 showed that PBMC T cells from metastatic melanoma patients had reduced CD71 upregulation compared with healthy controls, and this corresponded with multiple other functional defects in T cells from these patients. Harris D G Transferrin receptor (CD71) mediates the uptake of transferrin-iron complexes and is highly expressed on the surface of cells of the erythroid lineage. As to iTregs, FOXP3 was found to an important marker of natural CD4 + CD25 + regulatory T cells. described the presence of CD71 antigen on PMBC and SF Tregs in patients with RA. 1992 Apr;35(4):439-47. JM al, 2009) has shown reduced upregulation of CD95 in PBMC T cells from breast cancer patients following T cell activation in the presence of interferons, indicating the lack of full T cell activation under these conditions. Thus CD71 can be considered a mid-early activation marker as compared with late activation markers that are not appreciably upregulated until even later time points. Shipkova M, Wieland E.  Clin Chim Acta. Hyman Comparison of Immunohistochemical Staining Patterns for CD71, Hemoglobin, and CD235a in Normal and Neoplastic Bone Marrow Biopsy Specimens*. CD71 overexpression has been correlated with tumor stage in several cancer types (15,21), thereby suggesting CD71 as a marker for tumor diagnosis and progression (15,17). CD71 was the most useful marker in assessing the percentage of erythroid elements in acute erythroid/myeloid leukemia (FAB AML-M6a).

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