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Negative selection in the thymus includes semimature T cells.

Kishimoto H, Sprent J - J. Exp. Med. (1997)

Bottom Line: This paradox is resolved by the finding that medullary T cells (CD4+8- thymocytes) comprise two distinct subsets.Medullary thymocytes expressing a fully mature (HSAlo) phenotype are strongly resistant to tolerance induction, whereas cells with a semimature (HSAhi) phenotype are tolerance susceptible.These findings suggest that the differentiated T cells reaching the medulla from the cortex remain sensitive to tolerance induction for a brief period before acquiring a fully mature tolerance-resistant phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, IMM4, The Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
The thymic medulla plays a key role in negative selection (self-tolerance induction) and contains differentiated T cells en route to the extrathymic environment. However, being relatively mature, medullary T cells are thought to be beyond the stage of tolerance induction. This paradox is resolved by the finding that medullary T cells (CD4+8- thymocytes) comprise two distinct subsets. Medullary thymocytes expressing a fully mature (HSAlo) phenotype are strongly resistant to tolerance induction, whereas cells with a semimature (HSAhi) phenotype are tolerance susceptible. These findings suggest that the differentiated T cells reaching the medulla from the cortex remain sensitive to tolerance induction for a brief period before acquiring a fully mature tolerance-resistant phenotype. The semimature subset of medullarsy T cells displays unique requirements for tolerance induction; depending upon the conditions used, tolerizing these cells can involve either a Fas (CD95)-dependent or a Fas-independent pathway.

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Effect of Fas (CD95) on negative selection of thymocyte subpopulations. (A) Purified cells from B6 or B6 lpr/lpr mice were cultured  for 20 h on plates coated with either anti-TCR mAb alone (20 μg/ml) or  with anti-TCR (10 μg/ml) plus anti-CD28 (20 μg/ml) mAb. Where indicated, Fas–Ig fusion protein (provided by Dr. D. Lynch; 10 μg/ml) was  added to the cultures. (B) Relative sensitivity of normal B6 and B6 lpr/lpr  CD4+8+ and HSAhi CD4+8− cells to TCR–CD28-mediated apoptosis in  vitro. Cells were cultured for 20 h on plates coated with various concentrations of anti-TCR mAb ± a fixed concentration of anti-CD28 mAb as  described in Fig. 3. Apoptosis was measured by TUNEL staining. The  data represent the mean of two separate experiments.
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Figure 4: Effect of Fas (CD95) on negative selection of thymocyte subpopulations. (A) Purified cells from B6 or B6 lpr/lpr mice were cultured for 20 h on plates coated with either anti-TCR mAb alone (20 μg/ml) or with anti-TCR (10 μg/ml) plus anti-CD28 (20 μg/ml) mAb. Where indicated, Fas–Ig fusion protein (provided by Dr. D. Lynch; 10 μg/ml) was added to the cultures. (B) Relative sensitivity of normal B6 and B6 lpr/lpr CD4+8+ and HSAhi CD4+8− cells to TCR–CD28-mediated apoptosis in vitro. Cells were cultured for 20 h on plates coated with various concentrations of anti-TCR mAb ± a fixed concentration of anti-CD28 mAb as described in Fig. 3. Apoptosis was measured by TUNEL staining. The data represent the mean of two separate experiments.

Mentions: It is well accepted that activation-induced cell death of mature postthymic T cells is largely Fas-mediated and reflects contact with Fas ligand (FasL) (33–38). However, to date there is no clear evidence that Fas plays a role in negative selection in the thymus (39, 40). In agreement with this view, TCR–CD28-mediated apoptosis of immature CD4+8+ thymocytes could not be blocked with a soluble Fas fusion protein (Fas–Ig) (41) and was unimpaired when CD4+8+ thymocytes were prepared from Fas-deficient B6 lpr/lpr mice (Fig. 4 A). Interestingly, however, TCR– CD28-mediated apoptosis of semimature HSAhi CD4+8− cells was abolished by Fas–Ig and was almost undetectable with cells from B6 lpr/lpr mice. These findings also applied to ligation with TCR alone (Fig. 4 A).


Negative selection in the thymus includes semimature T cells.

Kishimoto H, Sprent J - J. Exp. Med. (1997)

Effect of Fas (CD95) on negative selection of thymocyte subpopulations. (A) Purified cells from B6 or B6 lpr/lpr mice were cultured  for 20 h on plates coated with either anti-TCR mAb alone (20 μg/ml) or  with anti-TCR (10 μg/ml) plus anti-CD28 (20 μg/ml) mAb. Where indicated, Fas–Ig fusion protein (provided by Dr. D. Lynch; 10 μg/ml) was  added to the cultures. (B) Relative sensitivity of normal B6 and B6 lpr/lpr  CD4+8+ and HSAhi CD4+8− cells to TCR–CD28-mediated apoptosis in  vitro. Cells were cultured for 20 h on plates coated with various concentrations of anti-TCR mAb ± a fixed concentration of anti-CD28 mAb as  described in Fig. 3. Apoptosis was measured by TUNEL staining. The  data represent the mean of two separate experiments.
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Related In: Results  -  Collection

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Figure 4: Effect of Fas (CD95) on negative selection of thymocyte subpopulations. (A) Purified cells from B6 or B6 lpr/lpr mice were cultured for 20 h on plates coated with either anti-TCR mAb alone (20 μg/ml) or with anti-TCR (10 μg/ml) plus anti-CD28 (20 μg/ml) mAb. Where indicated, Fas–Ig fusion protein (provided by Dr. D. Lynch; 10 μg/ml) was added to the cultures. (B) Relative sensitivity of normal B6 and B6 lpr/lpr CD4+8+ and HSAhi CD4+8− cells to TCR–CD28-mediated apoptosis in vitro. Cells were cultured for 20 h on plates coated with various concentrations of anti-TCR mAb ± a fixed concentration of anti-CD28 mAb as described in Fig. 3. Apoptosis was measured by TUNEL staining. The data represent the mean of two separate experiments.
Mentions: It is well accepted that activation-induced cell death of mature postthymic T cells is largely Fas-mediated and reflects contact with Fas ligand (FasL) (33–38). However, to date there is no clear evidence that Fas plays a role in negative selection in the thymus (39, 40). In agreement with this view, TCR–CD28-mediated apoptosis of immature CD4+8+ thymocytes could not be blocked with a soluble Fas fusion protein (Fas–Ig) (41) and was unimpaired when CD4+8+ thymocytes were prepared from Fas-deficient B6 lpr/lpr mice (Fig. 4 A). Interestingly, however, TCR– CD28-mediated apoptosis of semimature HSAhi CD4+8− cells was abolished by Fas–Ig and was almost undetectable with cells from B6 lpr/lpr mice. These findings also applied to ligation with TCR alone (Fig. 4 A).

Bottom Line: This paradox is resolved by the finding that medullary T cells (CD4+8- thymocytes) comprise two distinct subsets.Medullary thymocytes expressing a fully mature (HSAlo) phenotype are strongly resistant to tolerance induction, whereas cells with a semimature (HSAhi) phenotype are tolerance susceptible.These findings suggest that the differentiated T cells reaching the medulla from the cortex remain sensitive to tolerance induction for a brief period before acquiring a fully mature tolerance-resistant phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, IMM4, The Scripps Research Institute, La Jolla, California 92037, USA.

ABSTRACT
The thymic medulla plays a key role in negative selection (self-tolerance induction) and contains differentiated T cells en route to the extrathymic environment. However, being relatively mature, medullary T cells are thought to be beyond the stage of tolerance induction. This paradox is resolved by the finding that medullary T cells (CD4+8- thymocytes) comprise two distinct subsets. Medullary thymocytes expressing a fully mature (HSAlo) phenotype are strongly resistant to tolerance induction, whereas cells with a semimature (HSAhi) phenotype are tolerance susceptible. These findings suggest that the differentiated T cells reaching the medulla from the cortex remain sensitive to tolerance induction for a brief period before acquiring a fully mature tolerance-resistant phenotype. The semimature subset of medullarsy T cells displays unique requirements for tolerance induction; depending upon the conditions used, tolerizing these cells can involve either a Fas (CD95)-dependent or a Fas-independent pathway.

Show MeSH
Related in: MedlinePlus