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Several different cell surface molecules control negative selection of medullary thymocytes.

Kishimoto H, Sprent J - J. Exp. Med. (1999)

Bottom Line: In support of this idea, we show here that at least three cell surface molecules, namely CD28, CD5, and CD43, contribute to Fas-independent negative selection of the tolerance-susceptible population of heat-stable antigen (HSA)hiCD4+8- cells found in the medulla.The costimulatory function of these three molecules can be blocked by certain cytokines, IL-4 and IL-7, and coinjecting these cytokines with antigen in vivo abolishes negative selection; Fas-dependent negative selection, however, is maintained.The results suggest that efficient negative selection requires the combined functions of at least four cell surface molecules: CD28, CD5, CD43, and Fas.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
Repeated attempts to show that costimulation for negative selection is controlled by a single cell surface molecule have been unsuccessful. Thus, negative selection may involve multiple cell surface molecules acting in consort. In support of this idea, we show here that at least three cell surface molecules, namely CD28, CD5, and CD43, contribute to Fas-independent negative selection of the tolerance-susceptible population of heat-stable antigen (HSA)hiCD4+8- cells found in the medulla. The costimulatory function of these three molecules can be blocked by certain cytokines, IL-4 and IL-7, and coinjecting these cytokines with antigen in vivo abolishes negative selection; Fas-dependent negative selection, however, is maintained. The results suggest that efficient negative selection requires the combined functions of at least four cell surface molecules: CD28, CD5, CD43, and Fas.

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Capacity of IL-4 to abolish Fas-independent but not Fas-dependent negative selection to SEB in vivo. Neonatal (2-d-old) C3H/HeJ mice were injected intraperitoneally with PBS or the indicated amount of SEB plus/minus 40,000 U of IL-4; thymi were removed on day 2. Thymocyte suspensions were counted and four-color stained for CD4, CD8, HSA, and Vβ8 or Vβ6 expression and FACS™ analyzed (see Materials and Methods). (A) Representative data showing CD4/CD8 expression on whole thymocytes, Vβ8 expression on gated CD4+8− cells, and HSA expression on gated Vβ8+CD4+8− cells; percentages positive cells are shown. Data in parentheses refer to mean total numbers of viable thymocytes per mouse (three mice per group). (B) Data show total numbers of Vβ8+ and Vβ6+ cells per mouse at the level of semimature HSAhiCD4+8− cells and fully mature HSAloCD4+8− cells.
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Figure 6: Capacity of IL-4 to abolish Fas-independent but not Fas-dependent negative selection to SEB in vivo. Neonatal (2-d-old) C3H/HeJ mice were injected intraperitoneally with PBS or the indicated amount of SEB plus/minus 40,000 U of IL-4; thymi were removed on day 2. Thymocyte suspensions were counted and four-color stained for CD4, CD8, HSA, and Vβ8 or Vβ6 expression and FACS™ analyzed (see Materials and Methods). (A) Representative data showing CD4/CD8 expression on whole thymocytes, Vβ8 expression on gated CD4+8− cells, and HSA expression on gated Vβ8+CD4+8− cells; percentages positive cells are shown. Data in parentheses refer to mean total numbers of viable thymocytes per mouse (three mice per group). (B) Data show total numbers of Vβ8+ and Vβ6+ cells per mouse at the level of semimature HSAhiCD4+8− cells and fully mature HSAloCD4+8− cells.

Mentions: The effects of injecting SEB plus/minus 40,000 U of IL-4 into neonatal normal C3H/HeJ mice are shown in Fig. 6; C3H/HeJ (IAkIEk) rather than B6 (IAbIE−) mice were used because SEB is presented by IE much more effectively than by IA molecules. Confirming previous findings 27, injection of a moderate dose of 1 μg SEB without IL-4, i.e., a dose of SEB that induces Fas-independent negative selection, caused selective removal of Vβ8+HSAhiCD4+8− cells when measured on day 2 after injection (Fig. 6 A); data on total numbers of Vβ8+ cells per thymus (and Vβ6+ cells as a control) are shown in Fig. 6 B. Note that, because of expansion of fully mature HSAloCD4+8− cells, negative selection is not apparent at the level of CD4+8− thymocytes unless these cells are typed for HSA expression; the elimination of HSAhi cells reflects deletion rather than maturation into HSAlo cells 27.


Several different cell surface molecules control negative selection of medullary thymocytes.

Kishimoto H, Sprent J - J. Exp. Med. (1999)

Capacity of IL-4 to abolish Fas-independent but not Fas-dependent negative selection to SEB in vivo. Neonatal (2-d-old) C3H/HeJ mice were injected intraperitoneally with PBS or the indicated amount of SEB plus/minus 40,000 U of IL-4; thymi were removed on day 2. Thymocyte suspensions were counted and four-color stained for CD4, CD8, HSA, and Vβ8 or Vβ6 expression and FACS™ analyzed (see Materials and Methods). (A) Representative data showing CD4/CD8 expression on whole thymocytes, Vβ8 expression on gated CD4+8− cells, and HSA expression on gated Vβ8+CD4+8− cells; percentages positive cells are shown. Data in parentheses refer to mean total numbers of viable thymocytes per mouse (three mice per group). (B) Data show total numbers of Vβ8+ and Vβ6+ cells per mouse at the level of semimature HSAhiCD4+8− cells and fully mature HSAloCD4+8− cells.
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Figure 6: Capacity of IL-4 to abolish Fas-independent but not Fas-dependent negative selection to SEB in vivo. Neonatal (2-d-old) C3H/HeJ mice were injected intraperitoneally with PBS or the indicated amount of SEB plus/minus 40,000 U of IL-4; thymi were removed on day 2. Thymocyte suspensions were counted and four-color stained for CD4, CD8, HSA, and Vβ8 or Vβ6 expression and FACS™ analyzed (see Materials and Methods). (A) Representative data showing CD4/CD8 expression on whole thymocytes, Vβ8 expression on gated CD4+8− cells, and HSA expression on gated Vβ8+CD4+8− cells; percentages positive cells are shown. Data in parentheses refer to mean total numbers of viable thymocytes per mouse (three mice per group). (B) Data show total numbers of Vβ8+ and Vβ6+ cells per mouse at the level of semimature HSAhiCD4+8− cells and fully mature HSAloCD4+8− cells.
Mentions: The effects of injecting SEB plus/minus 40,000 U of IL-4 into neonatal normal C3H/HeJ mice are shown in Fig. 6; C3H/HeJ (IAkIEk) rather than B6 (IAbIE−) mice were used because SEB is presented by IE much more effectively than by IA molecules. Confirming previous findings 27, injection of a moderate dose of 1 μg SEB without IL-4, i.e., a dose of SEB that induces Fas-independent negative selection, caused selective removal of Vβ8+HSAhiCD4+8− cells when measured on day 2 after injection (Fig. 6 A); data on total numbers of Vβ8+ cells per thymus (and Vβ6+ cells as a control) are shown in Fig. 6 B. Note that, because of expansion of fully mature HSAloCD4+8− cells, negative selection is not apparent at the level of CD4+8− thymocytes unless these cells are typed for HSA expression; the elimination of HSAhi cells reflects deletion rather than maturation into HSAlo cells 27.

Bottom Line: In support of this idea, we show here that at least three cell surface molecules, namely CD28, CD5, and CD43, contribute to Fas-independent negative selection of the tolerance-susceptible population of heat-stable antigen (HSA)hiCD4+8- cells found in the medulla.The costimulatory function of these three molecules can be blocked by certain cytokines, IL-4 and IL-7, and coinjecting these cytokines with antigen in vivo abolishes negative selection; Fas-dependent negative selection, however, is maintained.The results suggest that efficient negative selection requires the combined functions of at least four cell surface molecules: CD28, CD5, CD43, and Fas.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
Repeated attempts to show that costimulation for negative selection is controlled by a single cell surface molecule have been unsuccessful. Thus, negative selection may involve multiple cell surface molecules acting in consort. In support of this idea, we show here that at least three cell surface molecules, namely CD28, CD5, and CD43, contribute to Fas-independent negative selection of the tolerance-susceptible population of heat-stable antigen (HSA)hiCD4+8- cells found in the medulla. The costimulatory function of these three molecules can be blocked by certain cytokines, IL-4 and IL-7, and coinjecting these cytokines with antigen in vivo abolishes negative selection; Fas-dependent negative selection, however, is maintained. The results suggest that efficient negative selection requires the combined functions of at least four cell surface molecules: CD28, CD5, CD43, and Fas.

Show MeSH
Related in: MedlinePlus