T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency

I Brigida, M Zoccolillo, MP Cicalese, L Pfajfer, Federica Barzaghi, S Scala, C Oleaga-Quintas, JA Álvarez-Álvarez, L Sereni, S Giannelli, C Sartirana, F Dionisio, L Pavesi, M Benavides-Nieto, L Basso-Ricci, P Capasso, Benedetta Mazzi, J Rosain, N Marcus, YN LeeR Somech, M Degano, G Raiola, R Caorsi, P Picco, MM Velez, J Khourieh, AA Arias, A Bousfiha, T Issekutz, A Issekutz, B Boisson, K Dobbs, A Villa, A Lombardo, B Neven, D Moshous, JL Casanova, JL Franco, LD Notarangelo, C Scielzo, S Volpi, L Dupré, J Bustamante, M Gattorno, A Aiuti

Research output: Contribution to journalArticle

Abstract

ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper–immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-a2directed migration. Gene transfer of ARPC1B in patients’ T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD81 T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID. © 2018 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)2362-2374
Number of pages13
JournalBlood
Volume132
Issue number22
DOIs
Publication statusPublished - 2018

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T-cells
Germ-Line Mutation
T-Lymphocytes
Defects
T-Cell Antigen Receptor
Actins
Immunological Synapses
Gene transfer
Lymphopenia
Pseudopodia
Idiopathic Thrombocytopenic Purpura
Lymphocytes
Flow cytometry
Confocal microscopy
Cell proliferation
Platelets
Cytoskeleton
Confocal Microscopy
Cell Movement
Flow Cytometry

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T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency. / Brigida, I; Zoccolillo, M; Cicalese, MP; Pfajfer, L; Barzaghi, Federica; Scala, S; Oleaga-Quintas, C; Álvarez-Álvarez, JA; Sereni, L; Giannelli, S; Sartirana, C; Dionisio, F; Pavesi, L; Benavides-Nieto, M; Basso-Ricci, L; Capasso, P; Mazzi, Benedetta; Rosain, J; Marcus, N; Lee, YN; Somech, R; Degano, M; Raiola, G; Caorsi, R; Picco, P; Velez, MM; Khourieh, J; Arias, AA; Bousfiha, A; Issekutz, T; Issekutz, A; Boisson, B; Dobbs, K; Villa, A; Lombardo, A; Neven, B; Moshous, D; Casanova, JL; Franco, JL; Notarangelo, LD; Scielzo, C; Volpi, S; Dupré, L; Bustamante, J; Gattorno, M; Aiuti, A.

In: Blood, Vol. 132, No. 22, 2018, p. 2362-2374.

Research output: Contribution to journalArticle

Brigida, I, Zoccolillo, M, Cicalese, MP, Pfajfer, L, Barzaghi, F, Scala, S, Oleaga-Quintas, C, Álvarez-Álvarez, JA, Sereni, L, Giannelli, S, Sartirana, C, Dionisio, F, Pavesi, L, Benavides-Nieto, M, Basso-Ricci, L, Capasso, P, Mazzi, B, Rosain, J, Marcus, N, Lee, YN, Somech, R, Degano, M, Raiola, G, Caorsi, R, Picco, P, Velez, MM, Khourieh, J, Arias, AA, Bousfiha, A, Issekutz, T, Issekutz, A, Boisson, B, Dobbs, K, Villa, A, Lombardo, A, Neven, B, Moshous, D, Casanova, JL, Franco, JL, Notarangelo, LD, Scielzo, C, Volpi, S, Dupré, L, Bustamante, J, Gattorno, M & Aiuti, A 2018, 'T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency', Blood, vol. 132, no. 22, pp. 2362-2374. https://doi.org/10.1182/blood-2018-07-863431
Brigida, I ; Zoccolillo, M ; Cicalese, MP ; Pfajfer, L ; Barzaghi, Federica ; Scala, S ; Oleaga-Quintas, C ; Álvarez-Álvarez, JA ; Sereni, L ; Giannelli, S ; Sartirana, C ; Dionisio, F ; Pavesi, L ; Benavides-Nieto, M ; Basso-Ricci, L ; Capasso, P ; Mazzi, Benedetta ; Rosain, J ; Marcus, N ; Lee, YN ; Somech, R ; Degano, M ; Raiola, G ; Caorsi, R ; Picco, P ; Velez, MM ; Khourieh, J ; Arias, AA ; Bousfiha, A ; Issekutz, T ; Issekutz, A ; Boisson, B ; Dobbs, K ; Villa, A ; Lombardo, A ; Neven, B ; Moshous, D ; Casanova, JL ; Franco, JL ; Notarangelo, LD ; Scielzo, C ; Volpi, S ; Dupré, L ; Bustamante, J ; Gattorno, M ; Aiuti, A. / T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency. In: Blood. 2018 ; Vol. 132, No. 22. pp. 2362-2374.
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abstract = "ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of na{\"i}ve T cells, and hyper–immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-a2directed migration. Gene transfer of ARPC1B in patients’ T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD81 T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID. {\circledC} 2018 by The American Society of Hematology.",
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T1 - T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency

AU - Brigida, I

AU - Zoccolillo, M

AU - Cicalese, MP

AU - Pfajfer, L

AU - Barzaghi, Federica

AU - Scala, S

AU - Oleaga-Quintas, C

AU - Álvarez-Álvarez, JA

AU - Sereni, L

AU - Giannelli, S

AU - Sartirana, C

AU - Dionisio, F

AU - Pavesi, L

AU - Benavides-Nieto, M

AU - Basso-Ricci, L

AU - Capasso, P

AU - Mazzi, Benedetta

AU - Rosain, J

AU - Marcus, N

AU - Lee, YN

AU - Somech, R

AU - Degano, M

AU - Raiola, G

AU - Caorsi, R

AU - Picco, P

AU - Velez, MM

AU - Khourieh, J

AU - Arias, AA

AU - Bousfiha, A

AU - Issekutz, T

AU - Issekutz, A

AU - Boisson, B

AU - Dobbs, K

AU - Villa, A

AU - Lombardo, A

AU - Neven, B

AU - Moshous, D

AU - Casanova, JL

AU - Franco, JL

AU - Notarangelo, LD

AU - Scielzo, C

AU - Volpi, S

AU - Dupré, L

AU - Bustamante, J

AU - Gattorno, M

AU - Aiuti, A

PY - 2018

Y1 - 2018

N2 - ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper–immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-a2directed migration. Gene transfer of ARPC1B in patients’ T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD81 T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID. © 2018 by The American Society of Hematology.

AB - ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper–immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-a2directed migration. Gene transfer of ARPC1B in patients’ T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD81 T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID. © 2018 by The American Society of Hematology.

U2 - 10.1182/blood-2018-07-863431

DO - 10.1182/blood-2018-07-863431

M3 - Article

VL - 132

SP - 2362

EP - 2374

JO - Blood

JF - Blood

SN - 0006-4971

IS - 22

ER -