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Negative selection in the thymus includes semimature T cells.

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

Bottom Line: However, being relatively mature, medullary T cells are thought to be beyond the stage of tolerance induction.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.

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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Negative selection  of HSAhi CD4+8− thymocytes in  vivo and in vitro. (A) Cell surface expression of HSA, Qa-2,  and CD69 on CD4+8− thymocytes after injection of antiTCR mAb, cortisone acetate, or  PBS; total numbers of thymocytes recovered are shown at  the left. (B) Cell surface expression of HSA on CD4+8− thymocytes recovered after culturing unseparated thymocytes for  20 h on plates coated with a  mixture of anti-TCR mAb (10  μg/ml) and anti-CD28 mAb (20  μg/ml) or on uncoated plates  (medium alone). Surface staining on viable (PI−) cells is  shown; the downregulation of  CD4 and CD8 on CD4+8+ cells  is typical of cells undergoing  early TCR-mediated apoptosis  (29); yields of total viable (PI−)  cells in the cultures were 85% for  cells cultured in medium alone  and 52% for cells cultured with  anti-TCR plus anti-CD28 mAbs.
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Figure 1: Negative selection of HSAhi CD4+8− thymocytes in vivo and in vitro. (A) Cell surface expression of HSA, Qa-2, and CD69 on CD4+8− thymocytes after injection of antiTCR mAb, cortisone acetate, or PBS; total numbers of thymocytes recovered are shown at the left. (B) Cell surface expression of HSA on CD4+8− thymocytes recovered after culturing unseparated thymocytes for 20 h on plates coated with a mixture of anti-TCR mAb (10 μg/ml) and anti-CD28 mAb (20 μg/ml) or on uncoated plates (medium alone). Surface staining on viable (PI−) cells is shown; the downregulation of CD4 and CD8 on CD4+8+ cells is typical of cells undergoing early TCR-mediated apoptosis (29); yields of total viable (PI−) cells in the cultures were 85% for cells cultured in medium alone and 52% for cells cultured with anti-TCR plus anti-CD28 mAbs.

Mentions: Acute negative selection of thymocytes can be induced by injecting mice with anti-TCR (or anti-CD3) mAb i.p. (30); in this model, costimulation is presumably provided by bystander APC (31, 32). As shown in Fig. 1 A, injecting mice with antiTCR mAb ablated immature CD4+8+ thymocytes by 48 h after injection and caused a reciprocal increase in SP CD4+8− and CD4−8+ cells. However, gating on CD4+8− cells at 48 h revealed that this population consisted almost entirely of fully mature HSAlo Qa-2hi CD69lo cells; the major subset of semimature HSAhi Qa-2lo CD69hi cells was virtually undetectable. These semimature T cells were prominent in normal (PBS-injected) mice and were not depleted after cortisone treatment. The data in Fig. 1 A refer to adult 8-wk-old mice. Essentially similar findings applied when anti-TCR mAb was injected into neonatal (1-wk-old) mice (data not shown). However, in this situation, the elimination of thymocytes was prominent for semimature HSAhi CD4+8− cells but not for CD4+8+ cells, suggesting that the destruction of CD4+8+ cells in adult mice (Fig. 1 A) was probably largely mediated by cytokines and/or increased steroid levels released via anti-TCR stimulation of mature postthymic T cells.


Negative selection in the thymus includes semimature T cells.

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

Negative selection  of HSAhi CD4+8− thymocytes in  vivo and in vitro. (A) Cell surface expression of HSA, Qa-2,  and CD69 on CD4+8− thymocytes after injection of antiTCR mAb, cortisone acetate, or  PBS; total numbers of thymocytes recovered are shown at  the left. (B) Cell surface expression of HSA on CD4+8− thymocytes recovered after culturing unseparated thymocytes for  20 h on plates coated with a  mixture of anti-TCR mAb (10  μg/ml) and anti-CD28 mAb (20  μg/ml) or on uncoated plates  (medium alone). Surface staining on viable (PI−) cells is  shown; the downregulation of  CD4 and CD8 on CD4+8+ cells  is typical of cells undergoing  early TCR-mediated apoptosis  (29); yields of total viable (PI−)  cells in the cultures were 85% for  cells cultured in medium alone  and 52% for cells cultured with  anti-TCR plus anti-CD28 mAbs.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196120&req=5

Figure 1: Negative selection of HSAhi CD4+8− thymocytes in vivo and in vitro. (A) Cell surface expression of HSA, Qa-2, and CD69 on CD4+8− thymocytes after injection of antiTCR mAb, cortisone acetate, or PBS; total numbers of thymocytes recovered are shown at the left. (B) Cell surface expression of HSA on CD4+8− thymocytes recovered after culturing unseparated thymocytes for 20 h on plates coated with a mixture of anti-TCR mAb (10 μg/ml) and anti-CD28 mAb (20 μg/ml) or on uncoated plates (medium alone). Surface staining on viable (PI−) cells is shown; the downregulation of CD4 and CD8 on CD4+8+ cells is typical of cells undergoing early TCR-mediated apoptosis (29); yields of total viable (PI−) cells in the cultures were 85% for cells cultured in medium alone and 52% for cells cultured with anti-TCR plus anti-CD28 mAbs.
Mentions: Acute negative selection of thymocytes can be induced by injecting mice with anti-TCR (or anti-CD3) mAb i.p. (30); in this model, costimulation is presumably provided by bystander APC (31, 32). As shown in Fig. 1 A, injecting mice with antiTCR mAb ablated immature CD4+8+ thymocytes by 48 h after injection and caused a reciprocal increase in SP CD4+8− and CD4−8+ cells. However, gating on CD4+8− cells at 48 h revealed that this population consisted almost entirely of fully mature HSAlo Qa-2hi CD69lo cells; the major subset of semimature HSAhi Qa-2lo CD69hi cells was virtually undetectable. These semimature T cells were prominent in normal (PBS-injected) mice and were not depleted after cortisone treatment. The data in Fig. 1 A refer to adult 8-wk-old mice. Essentially similar findings applied when anti-TCR mAb was injected into neonatal (1-wk-old) mice (data not shown). However, in this situation, the elimination of thymocytes was prominent for semimature HSAhi CD4+8− cells but not for CD4+8+ cells, suggesting that the destruction of CD4+8+ cells in adult mice (Fig. 1 A) was probably largely mediated by cytokines and/or increased steroid levels released via anti-TCR stimulation of mature postthymic T cells.

Bottom Line: However, being relatively mature, medullary T cells are thought to be beyond the stage of tolerance induction.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.

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