Regulation of NKT cell development by SAP, the protein defective in XLP

Kim E. Nichols; Jamie Hom; Shun You Gong; Arupa Ganguly; Cindy S. Ma; Jennifer L. Cannons; Stuart G. Tangye; Pamela L. Schwartzberg; Gary A. Koretzky; Paul L. Stein

doi:10.1038/nm1189

Regulation of NKT cell development by SAP, the protein defective in XLP

Kim E. Nichols^*, Jamie Hom, Shun You Gong, Arupa Ganguly, Cindy S. Ma, Jennifer L. Cannons, Stuart G. Tangye, Pamela L. Schwartzberg, Gary A. Koretzky, Paul L. Stein

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

327 Scopus citations

Abstract

The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity ^1-3. Here, we show that SAP, encoded by the SH2D1A gene locus, also has a crucial role during the development of NKT cells, a lymphocyte subset with immunoregulatory functions in response to infection, cancer and autoimmune disease⁴. Following stimulation with the NKT cell-specific agonist α-galactosyl ceramide (αGC), Sh2d1a^-/- splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell-dependent manner. While evaluating the abnormalities in αGC-induced immune responses, we observed that Sh2d1a^-/- animals lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a^-/- bone marrow cells. Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells. Furthermore, a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Thus, SAP is a crucial regulator of NKT cell ontogeny in humans and in mice. The absence of NKT cells may contribute to the phenotypes of SAP deficiency, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.

Original language	English (US)
Pages (from-to)	340-345
Number of pages	6
Journal	Nature Medicine
Volume	11
Issue number	3
DOIs	https://doi.org/10.1038/nm1189
State	Published - Mar 2005

Funding

We thank the patients who participated in this study. We are also grateful to R. Buckley, L. Silverman, A. Malbran, G. Uzel, S. Adelstein, R. Walls, F. Alvaro and D. Anderson for providing patient samples. We thank A. Bendelac for providing the Cd1d1–/– mice, W. Pear for the MIGR vector, M. Kronenberg and L. Sidobre for the αGC-loaded tetramer and the NKT cell hybridoma, L. Lanier for the Ly49D and Ly49G2 antibodies and Kirin Brewery for αGC. We acknowledge X. Zhong, M. Weiss,V. Shapiro and J. Stadanlick for their review of this manuscript, G. Bunin for assistance with statistics, and S. Jain for his technical assistance. This work was supported by the American Society of Hematology (K.E.N.), the Juvenile Diabetes Foundation, International (P.L.S.), the US National Institutes of Health (K.E.N., P.L.S.), the New South Wales Cancer Council (S.G.T.) and the University of Sydney, Australia (C.S.M.).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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@article{ef67bceee1d544f0ae66f9f7feacd874,

title = "Regulation of NKT cell development by SAP, the protein defective in XLP",

abstract = "The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity 1-3. Here, we show that SAP, encoded by the SH2D1A gene locus, also has a crucial role during the development of NKT cells, a lymphocyte subset with immunoregulatory functions in response to infection, cancer and autoimmune disease4. Following stimulation with the NKT cell-specific agonist α-galactosyl ceramide (αGC), Sh2d1a-/- splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell-dependent manner. While evaluating the abnormalities in αGC-induced immune responses, we observed that Sh2d1a-/- animals lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a-/- bone marrow cells. Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells. Furthermore, a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Thus, SAP is a crucial regulator of NKT cell ontogeny in humans and in mice. The absence of NKT cells may contribute to the phenotypes of SAP deficiency, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.",

author = "Nichols, {Kim E.} and Jamie Hom and Gong, {Shun You} and Arupa Ganguly and Ma, {Cindy S.} and Cannons, {Jennifer L.} and Tangye, {Stuart G.} and Schwartzberg, {Pamela L.} and Koretzky, {Gary A.} and Stein, {Paul L.}",

note = "Funding Information: We thank the patients who participated in this study. We are also grateful to R. Buckley, L. Silverman, A. Malbran, G. Uzel, S. Adelstein, R. Walls, F. Alvaro and D. Anderson for providing patient samples. We thank A. Bendelac for providing the Cd1d1–/– mice, W. Pear for the MIGR vector, M. Kronenberg and L. Sidobre for the αGC-loaded tetramer and the NKT cell hybridoma, L. Lanier for the Ly49D and Ly49G2 antibodies and Kirin Brewery for αGC. We acknowledge X. Zhong, M. Weiss,V. Shapiro and J. Stadanlick for their review of this manuscript, G. Bunin for assistance with statistics, and S. Jain for his technical assistance. This work was supported by the American Society of Hematology (K.E.N.), the Juvenile Diabetes Foundation, International (P.L.S.), the US National Institutes of Health (K.E.N., P.L.S.), the New South Wales Cancer Council (S.G.T.) and the University of Sydney, Australia (C.S.M.).",

year = "2005",

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doi = "10.1038/nm1189",

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T1 - Regulation of NKT cell development by SAP, the protein defective in XLP

AU - Nichols, Kim E.

AU - Hom, Jamie

AU - Gong, Shun You

AU - Ganguly, Arupa

AU - Ma, Cindy S.

AU - Cannons, Jennifer L.

AU - Tangye, Stuart G.

AU - Schwartzberg, Pamela L.

AU - Koretzky, Gary A.

AU - Stein, Paul L.

N1 - Funding Information: We thank the patients who participated in this study. We are also grateful to R. Buckley, L. Silverman, A. Malbran, G. Uzel, S. Adelstein, R. Walls, F. Alvaro and D. Anderson for providing patient samples. We thank A. Bendelac for providing the Cd1d1–/– mice, W. Pear for the MIGR vector, M. Kronenberg and L. Sidobre for the αGC-loaded tetramer and the NKT cell hybridoma, L. Lanier for the Ly49D and Ly49G2 antibodies and Kirin Brewery for αGC. We acknowledge X. Zhong, M. Weiss,V. Shapiro and J. Stadanlick for their review of this manuscript, G. Bunin for assistance with statistics, and S. Jain for his technical assistance. This work was supported by the American Society of Hematology (K.E.N.), the Juvenile Diabetes Foundation, International (P.L.S.), the US National Institutes of Health (K.E.N., P.L.S.), the New South Wales Cancer Council (S.G.T.) and the University of Sydney, Australia (C.S.M.).

PY - 2005/3

Y1 - 2005/3

N2 - The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity 1-3. Here, we show that SAP, encoded by the SH2D1A gene locus, also has a crucial role during the development of NKT cells, a lymphocyte subset with immunoregulatory functions in response to infection, cancer and autoimmune disease4. Following stimulation with the NKT cell-specific agonist α-galactosyl ceramide (αGC), Sh2d1a-/- splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell-dependent manner. While evaluating the abnormalities in αGC-induced immune responses, we observed that Sh2d1a-/- animals lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a-/- bone marrow cells. Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells. Furthermore, a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Thus, SAP is a crucial regulator of NKT cell ontogeny in humans and in mice. The absence of NKT cells may contribute to the phenotypes of SAP deficiency, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.

AB - The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity 1-3. Here, we show that SAP, encoded by the SH2D1A gene locus, also has a crucial role during the development of NKT cells, a lymphocyte subset with immunoregulatory functions in response to infection, cancer and autoimmune disease4. Following stimulation with the NKT cell-specific agonist α-galactosyl ceramide (αGC), Sh2d1a-/- splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell-dependent manner. While evaluating the abnormalities in αGC-induced immune responses, we observed that Sh2d1a-/- animals lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a-/- bone marrow cells. Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells. Furthermore, a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Thus, SAP is a crucial regulator of NKT cell ontogeny in humans and in mice. The absence of NKT cells may contribute to the phenotypes of SAP deficiency, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.

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Regulation of NKT cell development by SAP, the protein defective in XLP

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