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CD1-reactive natural killer T cells are required for development of systemic tolerance through an immune-privileged site.

Sonoda KH, Exley M, Snapper S, Balk SP, Stein-Streilein J - J. Exp. Med. (1999)

Bottom Line: Therefore, this model for immune-privileged site-mediated tolerance provided us with an excellent format for studying the role of NKT cells in the development of tolerance.Significantly, CD1-reactive NKT cells were not required for intravenously induced systemic tolerance, thereby establishing that different mechanisms mediate development of tolerance to antigens inoculated by these routes.A critical role for NKT cells in the development of systemic tolerance associated with an immune-privileged site suggests a mechanism involving NKT cells in self-tolerance and their defects in autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.

ABSTRACT
Systemic tolerance can be elicited by introducing antigen into an immune-privileged site, such as the eye, or directly into the blood. Both routes of immunization result in a selective deficiency of systemic delayed type hypersensitivity. Although the experimental animal model of anterior chamber-associated immune deviation (ACAID) occurs in most mouse strains, ACAID cannot be induced in several mutant mouse strains that are coincidentally deficient in natural killer T (NKT) cells. Therefore, this model for immune-privileged site-mediated tolerance provided us with an excellent format for studying the role of NKT cells in the development of tolerance. The following data show that CD1-reactive NKT cells are required for the development of systemic tolerance induced via the eye as follows: (a) CD1 knockout mice were unable to develop ACAID unless they were reconstituted with NKT cells together with CD1(+) antigen-presenting cells; (b) specific antibody depletion of NKT cells in vivo abrogated the development of ACAID; and (c) anti-CD1 monoclonal antibody treatment of wild-type mice prevented ACAID development. Significantly, CD1-reactive NKT cells were not required for intravenously induced systemic tolerance, thereby establishing that different mechanisms mediate development of tolerance to antigens inoculated by these routes. A critical role for NKT cells in the development of systemic tolerance associated with an immune-privileged site suggests a mechanism involving NKT cells in self-tolerance and their defects in autoimmunity.

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In vivo blocking of NKT cell–CD1 interaction abrogated the ACAID. Five B6 mice were inoculated intravenously with rat IgM or anti-CD1 (3C11) Abs 1 d before ac inoculation with OVA. 7 d later, column-enriched splenic T cells harvested from ac-inoculated mice (regulator) were cotransferred with effector and stimulator cells into the ear pinnae of naive syngeneic mice (five per group). Ear swelling measurements from B6 mice (24 h after ear challenge) are shown on the ordinate, and cell mixture inoculated is indicated below each bar on the abscissa. Significant differences (P ≤ 0.05) are indicated by an asterisk.
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Figure 6: In vivo blocking of NKT cell–CD1 interaction abrogated the ACAID. Five B6 mice were inoculated intravenously with rat IgM or anti-CD1 (3C11) Abs 1 d before ac inoculation with OVA. 7 d later, column-enriched splenic T cells harvested from ac-inoculated mice (regulator) were cotransferred with effector and stimulator cells into the ear pinnae of naive syngeneic mice (five per group). Ear swelling measurements from B6 mice (24 h after ear challenge) are shown on the ordinate, and cell mixture inoculated is indicated below each bar on the abscissa. Significant differences (P ≤ 0.05) are indicated by an asterisk.

Mentions: Clearly CD1 is needed for the development of NKT cells, but it is unknown if CD1 is required for NKT cell function in the generation of regulatory T cells in ACAID. We reasoned that if NKT cell interactions with CD1 were required for ACAID induction, we might be able to block ACAID by blocking the NKT cell interaction with CD1. Previously, anti-CD1 mAbs (3C11) were successfully used in vitro to block NKT cell–CD1 interactions 31. Therefore, mice were treated with anti-CD1 mAb 1 d before being inoculated (ac) with OVA and 8 d before harvesting the spleens, dissociating the cells, and column-enriching the splenic T cells for use as regulator cells in a LAT assay. 24 h after anti-CD1 treatment (3C11), dissociated spleen cells were stained with a different Ab for CD1 (1B1) to assess the presence of CD1+ cells in the spleen. Flow cytometry analyses showed that the Ab treatment did not alter the ratio or absolute number of CD1+ cells. In addition, anti-CD1 mAb treatment of mice did not alter the ratio or absolute number of NKT and NK cells (stained by anti–TCR-β and anti-NK1.1), T cells (stained by anti-CD3), B cells (stained by anti-B220), and macrophages (anti–Mac-1) in their spleens (data not shown). Groups of mice treated with control Ab developed antigen-specific efferent-regulatory T cells, but mice treated with anti-CD1 mAb did not (Fig. 6). Because the Ab treatment did not eliminate CD1+ cells, the most likely explanation is that an interaction between NKT cells and CD1 was blocked by the anti-CD1 mAb. Thus, we postulate that an interaction between the NKT cell and the CD1 molecule is required for the NKT cell to function in ACAID.


CD1-reactive natural killer T cells are required for development of systemic tolerance through an immune-privileged site.

Sonoda KH, Exley M, Snapper S, Balk SP, Stein-Streilein J - J. Exp. Med. (1999)

In vivo blocking of NKT cell–CD1 interaction abrogated the ACAID. Five B6 mice were inoculated intravenously with rat IgM or anti-CD1 (3C11) Abs 1 d before ac inoculation with OVA. 7 d later, column-enriched splenic T cells harvested from ac-inoculated mice (regulator) were cotransferred with effector and stimulator cells into the ear pinnae of naive syngeneic mice (five per group). Ear swelling measurements from B6 mice (24 h after ear challenge) are shown on the ordinate, and cell mixture inoculated is indicated below each bar on the abscissa. Significant differences (P ≤ 0.05) are indicated by an asterisk.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2195676&req=5

Figure 6: In vivo blocking of NKT cell–CD1 interaction abrogated the ACAID. Five B6 mice were inoculated intravenously with rat IgM or anti-CD1 (3C11) Abs 1 d before ac inoculation with OVA. 7 d later, column-enriched splenic T cells harvested from ac-inoculated mice (regulator) were cotransferred with effector and stimulator cells into the ear pinnae of naive syngeneic mice (five per group). Ear swelling measurements from B6 mice (24 h after ear challenge) are shown on the ordinate, and cell mixture inoculated is indicated below each bar on the abscissa. Significant differences (P ≤ 0.05) are indicated by an asterisk.
Mentions: Clearly CD1 is needed for the development of NKT cells, but it is unknown if CD1 is required for NKT cell function in the generation of regulatory T cells in ACAID. We reasoned that if NKT cell interactions with CD1 were required for ACAID induction, we might be able to block ACAID by blocking the NKT cell interaction with CD1. Previously, anti-CD1 mAbs (3C11) were successfully used in vitro to block NKT cell–CD1 interactions 31. Therefore, mice were treated with anti-CD1 mAb 1 d before being inoculated (ac) with OVA and 8 d before harvesting the spleens, dissociating the cells, and column-enriching the splenic T cells for use as regulator cells in a LAT assay. 24 h after anti-CD1 treatment (3C11), dissociated spleen cells were stained with a different Ab for CD1 (1B1) to assess the presence of CD1+ cells in the spleen. Flow cytometry analyses showed that the Ab treatment did not alter the ratio or absolute number of CD1+ cells. In addition, anti-CD1 mAb treatment of mice did not alter the ratio or absolute number of NKT and NK cells (stained by anti–TCR-β and anti-NK1.1), T cells (stained by anti-CD3), B cells (stained by anti-B220), and macrophages (anti–Mac-1) in their spleens (data not shown). Groups of mice treated with control Ab developed antigen-specific efferent-regulatory T cells, but mice treated with anti-CD1 mAb did not (Fig. 6). Because the Ab treatment did not eliminate CD1+ cells, the most likely explanation is that an interaction between NKT cells and CD1 was blocked by the anti-CD1 mAb. Thus, we postulate that an interaction between the NKT cell and the CD1 molecule is required for the NKT cell to function in ACAID.

Bottom Line: Therefore, this model for immune-privileged site-mediated tolerance provided us with an excellent format for studying the role of NKT cells in the development of tolerance.Significantly, CD1-reactive NKT cells were not required for intravenously induced systemic tolerance, thereby establishing that different mechanisms mediate development of tolerance to antigens inoculated by these routes.A critical role for NKT cells in the development of systemic tolerance associated with an immune-privileged site suggests a mechanism involving NKT cells in self-tolerance and their defects in autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.

ABSTRACT
Systemic tolerance can be elicited by introducing antigen into an immune-privileged site, such as the eye, or directly into the blood. Both routes of immunization result in a selective deficiency of systemic delayed type hypersensitivity. Although the experimental animal model of anterior chamber-associated immune deviation (ACAID) occurs in most mouse strains, ACAID cannot be induced in several mutant mouse strains that are coincidentally deficient in natural killer T (NKT) cells. Therefore, this model for immune-privileged site-mediated tolerance provided us with an excellent format for studying the role of NKT cells in the development of tolerance. The following data show that CD1-reactive NKT cells are required for the development of systemic tolerance induced via the eye as follows: (a) CD1 knockout mice were unable to develop ACAID unless they were reconstituted with NKT cells together with CD1(+) antigen-presenting cells; (b) specific antibody depletion of NKT cells in vivo abrogated the development of ACAID; and (c) anti-CD1 monoclonal antibody treatment of wild-type mice prevented ACAID development. Significantly, CD1-reactive NKT cells were not required for intravenously induced systemic tolerance, thereby establishing that different mechanisms mediate development of tolerance to antigens inoculated by these routes. A critical role for NKT cells in the development of systemic tolerance associated with an immune-privileged site suggests a mechanism involving NKT cells in self-tolerance and their defects in autoimmunity.

Show MeSH
Related in: MedlinePlus