Abstract
Surface proteins tethered to the membrane through a glycosylphosphatidylinositol (GPI) anchor are deficient in the blood cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) as result of a somatic mutation, in a hematopoietic stem cell, of the X-linked phosphatidylinositolglycan complementation group A (PIG-A) gene. In PNH patients, compared to the large numbers of GPI-deficient myeloid cells, the proportion of GPI-deficient lymphocytes tends to be low, and therefore the impact of GPI deficiency on immune function has been unclear. We have obtained complementation by Pig-a- embryonic stem (ES) cells of Rag-/- blastocysts, and we show that Pig-a- ES cells are able to reconstitute the T cell and B cell compartments of Rag-/- mice. Although these mice were immunologically competent, by comparison with appropriate controls we detected several abnormalities: (1) increased levels of IgG; (2) high frequency/titers of anti-nuclear antibodies; (3) markedly reduced delayed hypersensitivity; and (4) impaired activation-induced lymphocyte death in vitro. In some cases, aging Pig-a-/Rag-/- chimeric mice developed lymphadenopathy and polyclonal T cell and B cell expansion. Thus, GPI-linked proteins are not required for lymphocyte development but they are required for normal lymphocyte function and for maintaining normal peripheral lymphoid homeostasis.
| Original language | English |
|---|---|
| Pages (from-to) | 2607-2616 |
| Number of pages | 10 |
| Journal | European Journal of Immunology |
| Volume | 32 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sep 2002 |
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Keywords
- Complementation
- Knockout mouse
- Paroxysmal nocturnal hemoglobinuria
- Pig-a embryonic stem cell
- Rag mouse
ASJC Scopus subject areas
- Immunology
Cite this
Glycosylphosphatidylinositol-linked proteins are required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development. / Bessler, Monica; Rosti, Vittorio; Peng, Yufeng; Cattoretti, Giorgio; Notaro, Rosario; Ohsako, Satomi; Elkon, Keith B.; Luzzatto, Lucio.
In: European Journal of Immunology, Vol. 32, No. 9, 09.2002, p. 2607-2616.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glycosylphosphatidylinositol-linked proteins are required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development
AU - Bessler, Monica
AU - Rosti, Vittorio
AU - Peng, Yufeng
AU - Cattoretti, Giorgio
AU - Notaro, Rosario
AU - Ohsako, Satomi
AU - Elkon, Keith B.
AU - Luzzatto, Lucio
PY - 2002/9
Y1 - 2002/9
N2 - Surface proteins tethered to the membrane through a glycosylphosphatidylinositol (GPI) anchor are deficient in the blood cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) as result of a somatic mutation, in a hematopoietic stem cell, of the X-linked phosphatidylinositolglycan complementation group A (PIG-A) gene. In PNH patients, compared to the large numbers of GPI-deficient myeloid cells, the proportion of GPI-deficient lymphocytes tends to be low, and therefore the impact of GPI deficiency on immune function has been unclear. We have obtained complementation by Pig-a- embryonic stem (ES) cells of Rag-/- blastocysts, and we show that Pig-a- ES cells are able to reconstitute the T cell and B cell compartments of Rag-/- mice. Although these mice were immunologically competent, by comparison with appropriate controls we detected several abnormalities: (1) increased levels of IgG; (2) high frequency/titers of anti-nuclear antibodies; (3) markedly reduced delayed hypersensitivity; and (4) impaired activation-induced lymphocyte death in vitro. In some cases, aging Pig-a-/Rag-/- chimeric mice developed lymphadenopathy and polyclonal T cell and B cell expansion. Thus, GPI-linked proteins are not required for lymphocyte development but they are required for normal lymphocyte function and for maintaining normal peripheral lymphoid homeostasis.
AB - Surface proteins tethered to the membrane through a glycosylphosphatidylinositol (GPI) anchor are deficient in the blood cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) as result of a somatic mutation, in a hematopoietic stem cell, of the X-linked phosphatidylinositolglycan complementation group A (PIG-A) gene. In PNH patients, compared to the large numbers of GPI-deficient myeloid cells, the proportion of GPI-deficient lymphocytes tends to be low, and therefore the impact of GPI deficiency on immune function has been unclear. We have obtained complementation by Pig-a- embryonic stem (ES) cells of Rag-/- blastocysts, and we show that Pig-a- ES cells are able to reconstitute the T cell and B cell compartments of Rag-/- mice. Although these mice were immunologically competent, by comparison with appropriate controls we detected several abnormalities: (1) increased levels of IgG; (2) high frequency/titers of anti-nuclear antibodies; (3) markedly reduced delayed hypersensitivity; and (4) impaired activation-induced lymphocyte death in vitro. In some cases, aging Pig-a-/Rag-/- chimeric mice developed lymphadenopathy and polyclonal T cell and B cell expansion. Thus, GPI-linked proteins are not required for lymphocyte development but they are required for normal lymphocyte function and for maintaining normal peripheral lymphoid homeostasis.
KW - Complementation
KW - Knockout mouse
KW - Paroxysmal nocturnal hemoglobinuria
KW - Pig-a embryonic stem cell
KW - Rag mouse
UR - http://www.scopus.com/inward/record.url?scp=0036740354&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036740354&partnerID=8YFLogxK
U2 - 10.1002/1521-4141(200209)32:9<2607::AID-IMMU2607>3.0.CO;2-H
DO - 10.1002/1521-4141(200209)32:9<2607::AID-IMMU2607>3.0.CO;2-H
M3 - Article
C2 - 12207345
AN - SCOPUS:0036740354
VL - 32
SP - 2607
EP - 2616
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 9
ER -