Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment

Federica Cattaneo, Mike Recher, Stefania Masneri, Sachin N. Baxi, Claudia Fiorini, Francesca Antonelli, Christian A. Wysocki, Jose G. Calderon, Hermann Eibel, Angela R. Smith, Francisco A. Bonilla, Erdyni Tsitsikov, Silvia Giliani, Luigi D. Notarangelo, Sung Yun Pai

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype, with residual development and function of autologous T cells. Maternal T-cell engraftment is a common finding in infants with severe combined immunodeficiency but is not typically observed in patients with residual T-cell development. Objective: We sought to study in detail the molecular, cellular, and humoral immune phenotype and function of 3 patients with hypomorphic JAK3 mutations. Methods: We analyzed the distribution and function of T and B lymphocytes in 3 patients and studied the in vitro and in vivo responses of maternal T lymphocytes in 1 patient with maternal T-cell engraftment and residual production of autologous T lymphocytes. Results: B cells were present in normal numbers but with abnormal distribution of marginal zone-like and memory B cells. B-cell differentiation to plasmablasts in vitro in response to CD40 ligand and IL-21 was abolished. In 2 patients the T-cell repertoire was moderately restricted. Surprisingly, 1 patient showed coexistence of maternal and autologous T lymphocytes. By using an mAb recognizing the maternal noninherited HLA-A2 antigen, we found that autologous cells progressively accumulated in vivo but did not compete with maternal cells in vitro. Conclusion: The study of 3 patients with hypomorphic JAK3 mutations suggests that terminal B-cell maturation/differentiation requires intact JAK3 function, even if partially functioning T lymphocytes are present. Maternal T-cell engraftment can occur in patients with JAK3 mutations despite the presence of autologous T cells.

Original languageEnglish (US)
Pages (from-to)1136-1145
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Volume131
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Janus Kinase 3
Mothers
T-Lymphocytes
Mutation
B-Lymphocytes
Severe Combined Immunodeficiency
Cell Differentiation
Phenotype
HLA-A2 Antigen
CD40 Ligand

Keywords

  • cytokine signaling
  • maternal engraftment
  • Severe combined immunodeficiency

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment. / Cattaneo, Federica; Recher, Mike; Masneri, Stefania; Baxi, Sachin N.; Fiorini, Claudia; Antonelli, Francesca; Wysocki, Christian A.; Calderon, Jose G.; Eibel, Hermann; Smith, Angela R.; Bonilla, Francisco A.; Tsitsikov, Erdyni; Giliani, Silvia; Notarangelo, Luigi D.; Pai, Sung Yun.

In: Journal of Allergy and Clinical Immunology, Vol. 131, No. 4, 04.2013, p. 1136-1145.

Research output: Contribution to journalArticle

Cattaneo, F, Recher, M, Masneri, S, Baxi, SN, Fiorini, C, Antonelli, F, Wysocki, CA, Calderon, JG, Eibel, H, Smith, AR, Bonilla, FA, Tsitsikov, E, Giliani, S, Notarangelo, LD & Pai, SY 2013, 'Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment', Journal of Allergy and Clinical Immunology, vol. 131, no. 4, pp. 1136-1145. https://doi.org/10.1016/j.jaci.2012.12.667
Cattaneo, Federica ; Recher, Mike ; Masneri, Stefania ; Baxi, Sachin N. ; Fiorini, Claudia ; Antonelli, Francesca ; Wysocki, Christian A. ; Calderon, Jose G. ; Eibel, Hermann ; Smith, Angela R. ; Bonilla, Francisco A. ; Tsitsikov, Erdyni ; Giliani, Silvia ; Notarangelo, Luigi D. ; Pai, Sung Yun. / Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment. In: Journal of Allergy and Clinical Immunology. 2013 ; Vol. 131, No. 4. pp. 1136-1145.
@article{812c10245fa443b99d44261330b82594,
title = "Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment",
abstract = "Background: Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype, with residual development and function of autologous T cells. Maternal T-cell engraftment is a common finding in infants with severe combined immunodeficiency but is not typically observed in patients with residual T-cell development. Objective: We sought to study in detail the molecular, cellular, and humoral immune phenotype and function of 3 patients with hypomorphic JAK3 mutations. Methods: We analyzed the distribution and function of T and B lymphocytes in 3 patients and studied the in vitro and in vivo responses of maternal T lymphocytes in 1 patient with maternal T-cell engraftment and residual production of autologous T lymphocytes. Results: B cells were present in normal numbers but with abnormal distribution of marginal zone-like and memory B cells. B-cell differentiation to plasmablasts in vitro in response to CD40 ligand and IL-21 was abolished. In 2 patients the T-cell repertoire was moderately restricted. Surprisingly, 1 patient showed coexistence of maternal and autologous T lymphocytes. By using an mAb recognizing the maternal noninherited HLA-A2 antigen, we found that autologous cells progressively accumulated in vivo but did not compete with maternal cells in vitro. Conclusion: The study of 3 patients with hypomorphic JAK3 mutations suggests that terminal B-cell maturation/differentiation requires intact JAK3 function, even if partially functioning T lymphocytes are present. Maternal T-cell engraftment can occur in patients with JAK3 mutations despite the presence of autologous T cells.",
keywords = "cytokine signaling, maternal engraftment, Severe combined immunodeficiency",
author = "Federica Cattaneo and Mike Recher and Stefania Masneri and Baxi, {Sachin N.} and Claudia Fiorini and Francesca Antonelli and Wysocki, {Christian A.} and Calderon, {Jose G.} and Hermann Eibel and Smith, {Angela R.} and Bonilla, {Francisco A.} and Erdyni Tsitsikov and Silvia Giliani and Notarangelo, {Luigi D.} and Pai, {Sung Yun}",
year = "2013",
month = "4",
doi = "10.1016/j.jaci.2012.12.667",
language = "English (US)",
volume = "131",
pages = "1136--1145",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "4",

}

TY - JOUR

T1 - Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment

AU - Cattaneo, Federica

AU - Recher, Mike

AU - Masneri, Stefania

AU - Baxi, Sachin N.

AU - Fiorini, Claudia

AU - Antonelli, Francesca

AU - Wysocki, Christian A.

AU - Calderon, Jose G.

AU - Eibel, Hermann

AU - Smith, Angela R.

AU - Bonilla, Francisco A.

AU - Tsitsikov, Erdyni

AU - Giliani, Silvia

AU - Notarangelo, Luigi D.

AU - Pai, Sung Yun

PY - 2013/4

Y1 - 2013/4

N2 - Background: Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype, with residual development and function of autologous T cells. Maternal T-cell engraftment is a common finding in infants with severe combined immunodeficiency but is not typically observed in patients with residual T-cell development. Objective: We sought to study in detail the molecular, cellular, and humoral immune phenotype and function of 3 patients with hypomorphic JAK3 mutations. Methods: We analyzed the distribution and function of T and B lymphocytes in 3 patients and studied the in vitro and in vivo responses of maternal T lymphocytes in 1 patient with maternal T-cell engraftment and residual production of autologous T lymphocytes. Results: B cells were present in normal numbers but with abnormal distribution of marginal zone-like and memory B cells. B-cell differentiation to plasmablasts in vitro in response to CD40 ligand and IL-21 was abolished. In 2 patients the T-cell repertoire was moderately restricted. Surprisingly, 1 patient showed coexistence of maternal and autologous T lymphocytes. By using an mAb recognizing the maternal noninherited HLA-A2 antigen, we found that autologous cells progressively accumulated in vivo but did not compete with maternal cells in vitro. Conclusion: The study of 3 patients with hypomorphic JAK3 mutations suggests that terminal B-cell maturation/differentiation requires intact JAK3 function, even if partially functioning T lymphocytes are present. Maternal T-cell engraftment can occur in patients with JAK3 mutations despite the presence of autologous T cells.

AB - Background: Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype, with residual development and function of autologous T cells. Maternal T-cell engraftment is a common finding in infants with severe combined immunodeficiency but is not typically observed in patients with residual T-cell development. Objective: We sought to study in detail the molecular, cellular, and humoral immune phenotype and function of 3 patients with hypomorphic JAK3 mutations. Methods: We analyzed the distribution and function of T and B lymphocytes in 3 patients and studied the in vitro and in vivo responses of maternal T lymphocytes in 1 patient with maternal T-cell engraftment and residual production of autologous T lymphocytes. Results: B cells were present in normal numbers but with abnormal distribution of marginal zone-like and memory B cells. B-cell differentiation to plasmablasts in vitro in response to CD40 ligand and IL-21 was abolished. In 2 patients the T-cell repertoire was moderately restricted. Surprisingly, 1 patient showed coexistence of maternal and autologous T lymphocytes. By using an mAb recognizing the maternal noninherited HLA-A2 antigen, we found that autologous cells progressively accumulated in vivo but did not compete with maternal cells in vitro. Conclusion: The study of 3 patients with hypomorphic JAK3 mutations suggests that terminal B-cell maturation/differentiation requires intact JAK3 function, even if partially functioning T lymphocytes are present. Maternal T-cell engraftment can occur in patients with JAK3 mutations despite the presence of autologous T cells.

KW - cytokine signaling

KW - maternal engraftment

KW - Severe combined immunodeficiency

UR - http://www.scopus.com/inward/record.url?scp=84875735532&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875735532&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2012.12.667

DO - 10.1016/j.jaci.2012.12.667

M3 - Article

VL - 131

SP - 1136

EP - 1145

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 4

ER -