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A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.

Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, Bainter W, Fraulino D, Rahimov F, Sieff C, Liu ZJ, Alshemmari SH, Al-Ramadi BK, Al-Dhekri H, Arnaout R, Abu-Shukair M, Vatsayan A, Silver E, Ahuja S, Davies EG, Sola-Visner M, Ohsumi TK, Andrews NC, Notarangelo LD, Fleming MD, Al-Herz W, Kunkel LM, Geha RS - Nat. Genet. (2015)

Bottom Line: The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface.We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia.These findings demonstrate the importance of TfR1 in adaptive immunity.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.

ABSTRACT
Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.

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Lymphocyte dysfunction in Patients A1–A3 and B1(a) PBMC proliferation to phytohemagglutinin (PHA), anti-CD3 antibody (α-CD3), phorbol 12-myristate 13-acetate and ionomycin (PMA+IO), and tetanus toxoid antigen (TT). There were insufficient cells from Patient B1 for proliferation studies to TT. (b) B cell proliferation and IgG and IgE production to anti-CD40+IL-4 stimulation, and (c) molecular events in IgE switching as shown by PCR of B cell cDNA. GLT, germline transcript; AICDA, activation induced cytidine deaminase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase used as a house-keeping gene control. Patient B1 was not studied in these assays because of his lack of circulating B cells. Symbols represent individual patients (Pt) and controls (C). Graphs display means ± SEM; *P<0.05, **P<0.01, ***P<0.001.
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Figure 1: Lymphocyte dysfunction in Patients A1–A3 and B1(a) PBMC proliferation to phytohemagglutinin (PHA), anti-CD3 antibody (α-CD3), phorbol 12-myristate 13-acetate and ionomycin (PMA+IO), and tetanus toxoid antigen (TT). There were insufficient cells from Patient B1 for proliferation studies to TT. (b) B cell proliferation and IgG and IgE production to anti-CD40+IL-4 stimulation, and (c) molecular events in IgE switching as shown by PCR of B cell cDNA. GLT, germline transcript; AICDA, activation induced cytidine deaminase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase used as a house-keeping gene control. Patient B1 was not studied in these assays because of his lack of circulating B cells. Symbols represent individual patients (Pt) and controls (C). Graphs display means ± SEM; *P<0.05, **P<0.01, ***P<0.001.

Mentions: The numbers of circulating total (CD3+), helper (CD4+), and cytotoxic (CD8+) T cells, natural killer (CD3−CD16+/CD56+) cells, and B (CD19+) cells in the patients were normal or near normal. However, percentages of CD19+CD27+ memory B cells, important for antibody production, were significantly reduced (Supplementary Table 3). Proliferation of peripheral blood mononuclear cells (PBMCs) in response to the mitogen phytohemagglutinin (PHA), crosslinking of the T cell receptor (TCR) with anti-CD3 antibody, and phorbol 12-myristate 13-acetate and ionomycin (PMA+IO), which bypass the TCR, was significantly decreased in all four patients (Fig. 1a). T cell co-stimulation using anti-CD28 antibody or addition of IL-2 growth factor did not correct the defective TCR-driven proliferation, which was not associated with increased apoptosis (data not shown). These observations demonstrate a global defect in T cell proliferation.


A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency.

Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, Bainter W, Fraulino D, Rahimov F, Sieff C, Liu ZJ, Alshemmari SH, Al-Ramadi BK, Al-Dhekri H, Arnaout R, Abu-Shukair M, Vatsayan A, Silver E, Ahuja S, Davies EG, Sola-Visner M, Ohsumi TK, Andrews NC, Notarangelo LD, Fleming MD, Al-Herz W, Kunkel LM, Geha RS - Nat. Genet. (2015)

Lymphocyte dysfunction in Patients A1–A3 and B1(a) PBMC proliferation to phytohemagglutinin (PHA), anti-CD3 antibody (α-CD3), phorbol 12-myristate 13-acetate and ionomycin (PMA+IO), and tetanus toxoid antigen (TT). There were insufficient cells from Patient B1 for proliferation studies to TT. (b) B cell proliferation and IgG and IgE production to anti-CD40+IL-4 stimulation, and (c) molecular events in IgE switching as shown by PCR of B cell cDNA. GLT, germline transcript; AICDA, activation induced cytidine deaminase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase used as a house-keeping gene control. Patient B1 was not studied in these assays because of his lack of circulating B cells. Symbols represent individual patients (Pt) and controls (C). Graphs display means ± SEM; *P<0.05, **P<0.01, ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4696875&req=5

Figure 1: Lymphocyte dysfunction in Patients A1–A3 and B1(a) PBMC proliferation to phytohemagglutinin (PHA), anti-CD3 antibody (α-CD3), phorbol 12-myristate 13-acetate and ionomycin (PMA+IO), and tetanus toxoid antigen (TT). There were insufficient cells from Patient B1 for proliferation studies to TT. (b) B cell proliferation and IgG and IgE production to anti-CD40+IL-4 stimulation, and (c) molecular events in IgE switching as shown by PCR of B cell cDNA. GLT, germline transcript; AICDA, activation induced cytidine deaminase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase used as a house-keeping gene control. Patient B1 was not studied in these assays because of his lack of circulating B cells. Symbols represent individual patients (Pt) and controls (C). Graphs display means ± SEM; *P<0.05, **P<0.01, ***P<0.001.
Mentions: The numbers of circulating total (CD3+), helper (CD4+), and cytotoxic (CD8+) T cells, natural killer (CD3−CD16+/CD56+) cells, and B (CD19+) cells in the patients were normal or near normal. However, percentages of CD19+CD27+ memory B cells, important for antibody production, were significantly reduced (Supplementary Table 3). Proliferation of peripheral blood mononuclear cells (PBMCs) in response to the mitogen phytohemagglutinin (PHA), crosslinking of the T cell receptor (TCR) with anti-CD3 antibody, and phorbol 12-myristate 13-acetate and ionomycin (PMA+IO), which bypass the TCR, was significantly decreased in all four patients (Fig. 1a). T cell co-stimulation using anti-CD28 antibody or addition of IL-2 growth factor did not correct the defective TCR-driven proliferation, which was not associated with increased apoptosis (data not shown). These observations demonstrate a global defect in T cell proliferation.

Bottom Line: The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface.We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia.These findings demonstrate the importance of TfR1 in adaptive immunity.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.

ABSTRACT
Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.

Show MeSH
Related in: MedlinePlus