Glycosylation changes in hFUT1 transgenic mice increase TCR signaling and apoptosis resulting in thymocyte maturation arrest

Gregory Thomas Charles Moore, Steven J Brown, Adam C Winterhalter, Mark Lust, Evelyn J Salvaris, Carly Selan, Harshal Nandurkar, Paul V Desmond, Peter J Cowan, Anthony d'Apice

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

Glycosylation of cell surface proteins is important in thymocyte maturation. In particular, the level of sialylation of key glycoproteins such as CD45 is believed to play a major role in regulating TCR signaling, adhesion and apoptosis of developing thymocytes. We show here that transgenic expression of human alpha1-2 fucosyltransferase (hFUT1) in mice resulted in a marked shift from sialylation to fucosylation of thymocyte glycoproteins. This was associated with a significant reduction in thymocyte number, an increased rate of apoptosis in double positive and single positive thymocytes, and a maturation arrest at TCR-dependent developmental transitions reminiscent of CD45 deficiency. Indeed, CD45RB dimerization was elevated in hFUT1 thymocytes, consistent with its hyposialylation, and there was a corresponding increase in phosphorylation of the TCR-associated protein Lck. However, contrary to the reduced TCR signaling in CD45 null mice, basal and stimulated TCR signaling was higher in hFUT1 thymocytes than in wild type thymocytes. Our results therefore demonstrate that aberrant expression of a single glycosyltransferase can profoundly affect thymopoiesis, although the relative involvement of CD45-dependent and -independent mechanisms is yet to be determined.
Original languageEnglish
Pages (from-to)2401 - 2410
Number of pages10
JournalMolecular Immunology
Volume45
Issue number8
Publication statusPublished - 2008

Cite this

Moore, G. T. C., Brown, S. J., Winterhalter, A. C., Lust, M., Salvaris, E. J., Selan, C., ... d'Apice, A. (2008). Glycosylation changes in hFUT1 transgenic mice increase TCR signaling and apoptosis resulting in thymocyte maturation arrest. Molecular Immunology, 45(8), 2401 - 2410.
Moore, Gregory Thomas Charles ; Brown, Steven J ; Winterhalter, Adam C ; Lust, Mark ; Salvaris, Evelyn J ; Selan, Carly ; Nandurkar, Harshal ; Desmond, Paul V ; Cowan, Peter J ; d'Apice, Anthony. / Glycosylation changes in hFUT1 transgenic mice increase TCR signaling and apoptosis resulting in thymocyte maturation arrest. In: Molecular Immunology. 2008 ; Vol. 45, No. 8. pp. 2401 - 2410.
@article{3fd2437e8fb74373b8e7a253aca976ed,
title = "Glycosylation changes in hFUT1 transgenic mice increase TCR signaling and apoptosis resulting in thymocyte maturation arrest",
abstract = "Glycosylation of cell surface proteins is important in thymocyte maturation. In particular, the level of sialylation of key glycoproteins such as CD45 is believed to play a major role in regulating TCR signaling, adhesion and apoptosis of developing thymocytes. We show here that transgenic expression of human alpha1-2 fucosyltransferase (hFUT1) in mice resulted in a marked shift from sialylation to fucosylation of thymocyte glycoproteins. This was associated with a significant reduction in thymocyte number, an increased rate of apoptosis in double positive and single positive thymocytes, and a maturation arrest at TCR-dependent developmental transitions reminiscent of CD45 deficiency. Indeed, CD45RB dimerization was elevated in hFUT1 thymocytes, consistent with its hyposialylation, and there was a corresponding increase in phosphorylation of the TCR-associated protein Lck. However, contrary to the reduced TCR signaling in CD45 null mice, basal and stimulated TCR signaling was higher in hFUT1 thymocytes than in wild type thymocytes. Our results therefore demonstrate that aberrant expression of a single glycosyltransferase can profoundly affect thymopoiesis, although the relative involvement of CD45-dependent and -independent mechanisms is yet to be determined.",
author = "Moore, {Gregory Thomas Charles} and Brown, {Steven J} and Winterhalter, {Adam C} and Mark Lust and Salvaris, {Evelyn J} and Carly Selan and Harshal Nandurkar and Desmond, {Paul V} and Cowan, {Peter J} and Anthony d'Apice",
year = "2008",
language = "English",
volume = "45",
pages = "2401 -- 2410",
journal = "Molecular Immunology",
issn = "0161-5890",
publisher = "Elsevier",
number = "8",

}

Moore, GTC, Brown, SJ, Winterhalter, AC, Lust, M, Salvaris, EJ, Selan, C, Nandurkar, H, Desmond, PV, Cowan, PJ & d'Apice, A 2008, 'Glycosylation changes in hFUT1 transgenic mice increase TCR signaling and apoptosis resulting in thymocyte maturation arrest', Molecular Immunology, vol. 45, no. 8, pp. 2401 - 2410.

Glycosylation changes in hFUT1 transgenic mice increase TCR signaling and apoptosis resulting in thymocyte maturation arrest. / Moore, Gregory Thomas Charles; Brown, Steven J; Winterhalter, Adam C; Lust, Mark; Salvaris, Evelyn J; Selan, Carly; Nandurkar, Harshal; Desmond, Paul V; Cowan, Peter J; d'Apice, Anthony.

In: Molecular Immunology, Vol. 45, No. 8, 2008, p. 2401 - 2410.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Glycosylation changes in hFUT1 transgenic mice increase TCR signaling and apoptosis resulting in thymocyte maturation arrest

AU - Moore, Gregory Thomas Charles

AU - Brown, Steven J

AU - Winterhalter, Adam C

AU - Lust, Mark

AU - Salvaris, Evelyn J

AU - Selan, Carly

AU - Nandurkar, Harshal

AU - Desmond, Paul V

AU - Cowan, Peter J

AU - d'Apice, Anthony

PY - 2008

Y1 - 2008

N2 - Glycosylation of cell surface proteins is important in thymocyte maturation. In particular, the level of sialylation of key glycoproteins such as CD45 is believed to play a major role in regulating TCR signaling, adhesion and apoptosis of developing thymocytes. We show here that transgenic expression of human alpha1-2 fucosyltransferase (hFUT1) in mice resulted in a marked shift from sialylation to fucosylation of thymocyte glycoproteins. This was associated with a significant reduction in thymocyte number, an increased rate of apoptosis in double positive and single positive thymocytes, and a maturation arrest at TCR-dependent developmental transitions reminiscent of CD45 deficiency. Indeed, CD45RB dimerization was elevated in hFUT1 thymocytes, consistent with its hyposialylation, and there was a corresponding increase in phosphorylation of the TCR-associated protein Lck. However, contrary to the reduced TCR signaling in CD45 null mice, basal and stimulated TCR signaling was higher in hFUT1 thymocytes than in wild type thymocytes. Our results therefore demonstrate that aberrant expression of a single glycosyltransferase can profoundly affect thymopoiesis, although the relative involvement of CD45-dependent and -independent mechanisms is yet to be determined.

AB - Glycosylation of cell surface proteins is important in thymocyte maturation. In particular, the level of sialylation of key glycoproteins such as CD45 is believed to play a major role in regulating TCR signaling, adhesion and apoptosis of developing thymocytes. We show here that transgenic expression of human alpha1-2 fucosyltransferase (hFUT1) in mice resulted in a marked shift from sialylation to fucosylation of thymocyte glycoproteins. This was associated with a significant reduction in thymocyte number, an increased rate of apoptosis in double positive and single positive thymocytes, and a maturation arrest at TCR-dependent developmental transitions reminiscent of CD45 deficiency. Indeed, CD45RB dimerization was elevated in hFUT1 thymocytes, consistent with its hyposialylation, and there was a corresponding increase in phosphorylation of the TCR-associated protein Lck. However, contrary to the reduced TCR signaling in CD45 null mice, basal and stimulated TCR signaling was higher in hFUT1 thymocytes than in wild type thymocytes. Our results therefore demonstrate that aberrant expression of a single glycosyltransferase can profoundly affect thymopoiesis, although the relative involvement of CD45-dependent and -independent mechanisms is yet to be determined.

UR - http://www.ncbi.nlm.nih.gov/pubmed/18155296

M3 - Article

VL - 45

SP - 2401

EP - 2410

JO - Molecular Immunology

JF - Molecular Immunology

SN - 0161-5890

IS - 8

ER -