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Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules.

Kirberg J, Berns A, von Boehmer H - J. Exp. Med. (1997)

Bottom Line: To address this issue we used recombination-activating gene (Rag)-deficient H-2b mice expressing a transgenic TCR restricted by I-Ed class II MHC molecules.After engraftment with Rag-/- H-2d fetal thymi, CD4+8- peripheral T cells emerged.Our results show that in the absence, but not in the presence, of selecting MHC molecules, peripheral mature T cells are short lived and disappear within 7 wk, indicating that continuous contact of the TCR with selecting MHC molecules is required for survival of T cells.

View Article: PubMed Central - PubMed

Affiliation: Netherlands Cancer Institute, Division of Molecular Genetics, Amsterdam.

ABSTRACT
In the thymus, T cells are selected according to their T cell receptor (TCR) specificity. After positive selection, mature cells are exported from primary lymphoid organs to seed the secondary lymphoid tissue. An important question is whether survival of mature T cells is an intrinsic property or requires continuous survival signals, i.e., engagement of the TCR by major histocompatibility complex (MHC) molecules in the periphery, perhaps in a similar way as occurring during thymic positive selection. To address this issue we used recombination-activating gene (Rag)-deficient H-2b mice expressing a transgenic TCR restricted by I-Ed class II MHC molecules. After engraftment with Rag-/- H-2d fetal thymi, CD4+8- peripheral T cells emerged. These cells were isolated and transferred into immunodeficient hosts of H-2b or H-2d haplotype, some of the latter being common cytokine receptor gamma chain deficient to exclude rejection of H-2b donor cells by host natural killer cells. Our results show that in the absence, but not in the presence, of selecting MHC molecules, peripheral mature T cells are short lived and disappear within 7 wk, indicating that continuous contact of the TCR with selecting MHC molecules is required for survival of T cells.

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CD4+8− lymphocytes from H-2d thymus-grafted H-2b ABII TCR Rag−/− mice survive in H-2d NK cell–deficient adoptive hosts. 105  CD4+8− and 105 CD4−8low lymphocytes from H-2d Rag−/− fetal thymus–transplanted H-2b ABII TCR Rag−/− mice were adoptively transferred into  H-2b Rag−/− and H-2d Rag−/− IL-2Rγ−/− mice. 7 wk after transfer, cells from lymph nodes and spleen were analyzed as in Fig. 3. Calculated numbers  of 6.5+HSA− cells were 900, 13,500, 5,900, and 3 × 106 for CD4+8− and 600, 6,100, 7.6 × 105, and 1.5 × 106 for CD4−8low cells in unmanipulated  H-2d Rag−/− IL-2Rγ−/−, unmanipulated H-2b Rag−/− (not shown), injected H-2b Rag−/−, and injected H-2d Rag−/− IL-2Rγ−/− mice, respectively.  Expansion in Rag-deficient H-2d mice was consistent with previous data (41). We also performed this type of experiment with two thymectomized H-2d  Rag−/− IL-2Rγ−/− mice and obtained similar results.
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Figure 4: CD4+8− lymphocytes from H-2d thymus-grafted H-2b ABII TCR Rag−/− mice survive in H-2d NK cell–deficient adoptive hosts. 105 CD4+8− and 105 CD4−8low lymphocytes from H-2d Rag−/− fetal thymus–transplanted H-2b ABII TCR Rag−/− mice were adoptively transferred into H-2b Rag−/− and H-2d Rag−/− IL-2Rγ−/− mice. 7 wk after transfer, cells from lymph nodes and spleen were analyzed as in Fig. 3. Calculated numbers of 6.5+HSA− cells were 900, 13,500, 5,900, and 3 × 106 for CD4+8− and 600, 6,100, 7.6 × 105, and 1.5 × 106 for CD4−8low cells in unmanipulated H-2d Rag−/− IL-2Rγ−/−, unmanipulated H-2b Rag−/− (not shown), injected H-2b Rag−/−, and injected H-2d Rag−/− IL-2Rγ−/− mice, respectively. Expansion in Rag-deficient H-2d mice was consistent with previous data (41). We also performed this type of experiment with two thymectomized H-2d Rag−/− IL-2Rγ−/− mice and obtained similar results.

Mentions: Cell sorter–purified CD4+8− and CD4−8low cells from thymus-grafted H-2b ABII TCR Rag−/− mice were transferred into either H-2b or H-2d immunodeficient recipient mice. As shown in Fig. 3, no 6.5+CD4+8− cells could be detected in either H-2b nu/nu or H-2d nu/nu recipient mice 7 wk after transfer, whereas 6.5+CD4−8low cells were found in the H-2b but not H-2d recipients. (Similar results were obtained after transfer into H-2b Rag−/− or H-2d Rag−/− recipient mice, data not shown.) In terms of engraftment, this result would be compatible with the notion that the transferred cells expressing H-2b MHC molecules only, could engraft in H-2b hosts, but not in H-2d hosts because of rejection by host NK cells (28–30). To circumvent this problem, a similar transfer of cells from thymus-grafted H-2b ABII TCR Rag−/− mice was performed into H-2b Rag−/− and H-2d Rag−/− IL-2Rγ−/− mice, devoid of NK cells (16, 17). As shown in Fig. 4, 6.5+CD4+8− cells survived only in H-2d recipients, whereas 6.5+CD4−8low cells survived both in H-2b and H-2d recipients when analyzed 7 wk after transfer. Taken together, these results show that in H-2b recipients, NK cells do not reject the transferred cells as 6.5+CD4−8low cells survive, but 6.5+CD4+8− cells vanish due to the lack of H-2d MHC molecules. In contrast, 6.5+CD4+8− cells survive long term in the presence of H-2d MHC molecules once not rejected by NK cells. 6.5+CD4−8low cells survived then as well.


Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules.

Kirberg J, Berns A, von Boehmer H - J. Exp. Med. (1997)

CD4+8− lymphocytes from H-2d thymus-grafted H-2b ABII TCR Rag−/− mice survive in H-2d NK cell–deficient adoptive hosts. 105  CD4+8− and 105 CD4−8low lymphocytes from H-2d Rag−/− fetal thymus–transplanted H-2b ABII TCR Rag−/− mice were adoptively transferred into  H-2b Rag−/− and H-2d Rag−/− IL-2Rγ−/− mice. 7 wk after transfer, cells from lymph nodes and spleen were analyzed as in Fig. 3. Calculated numbers  of 6.5+HSA− cells were 900, 13,500, 5,900, and 3 × 106 for CD4+8− and 600, 6,100, 7.6 × 105, and 1.5 × 106 for CD4−8low cells in unmanipulated  H-2d Rag−/− IL-2Rγ−/−, unmanipulated H-2b Rag−/− (not shown), injected H-2b Rag−/−, and injected H-2d Rag−/− IL-2Rγ−/− mice, respectively.  Expansion in Rag-deficient H-2d mice was consistent with previous data (41). We also performed this type of experiment with two thymectomized H-2d  Rag−/− IL-2Rγ−/− mice and obtained similar results.
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Related In: Results  -  Collection

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Figure 4: CD4+8− lymphocytes from H-2d thymus-grafted H-2b ABII TCR Rag−/− mice survive in H-2d NK cell–deficient adoptive hosts. 105 CD4+8− and 105 CD4−8low lymphocytes from H-2d Rag−/− fetal thymus–transplanted H-2b ABII TCR Rag−/− mice were adoptively transferred into H-2b Rag−/− and H-2d Rag−/− IL-2Rγ−/− mice. 7 wk after transfer, cells from lymph nodes and spleen were analyzed as in Fig. 3. Calculated numbers of 6.5+HSA− cells were 900, 13,500, 5,900, and 3 × 106 for CD4+8− and 600, 6,100, 7.6 × 105, and 1.5 × 106 for CD4−8low cells in unmanipulated H-2d Rag−/− IL-2Rγ−/−, unmanipulated H-2b Rag−/− (not shown), injected H-2b Rag−/−, and injected H-2d Rag−/− IL-2Rγ−/− mice, respectively. Expansion in Rag-deficient H-2d mice was consistent with previous data (41). We also performed this type of experiment with two thymectomized H-2d Rag−/− IL-2Rγ−/− mice and obtained similar results.
Mentions: Cell sorter–purified CD4+8− and CD4−8low cells from thymus-grafted H-2b ABII TCR Rag−/− mice were transferred into either H-2b or H-2d immunodeficient recipient mice. As shown in Fig. 3, no 6.5+CD4+8− cells could be detected in either H-2b nu/nu or H-2d nu/nu recipient mice 7 wk after transfer, whereas 6.5+CD4−8low cells were found in the H-2b but not H-2d recipients. (Similar results were obtained after transfer into H-2b Rag−/− or H-2d Rag−/− recipient mice, data not shown.) In terms of engraftment, this result would be compatible with the notion that the transferred cells expressing H-2b MHC molecules only, could engraft in H-2b hosts, but not in H-2d hosts because of rejection by host NK cells (28–30). To circumvent this problem, a similar transfer of cells from thymus-grafted H-2b ABII TCR Rag−/− mice was performed into H-2b Rag−/− and H-2d Rag−/− IL-2Rγ−/− mice, devoid of NK cells (16, 17). As shown in Fig. 4, 6.5+CD4+8− cells survived only in H-2d recipients, whereas 6.5+CD4−8low cells survived both in H-2b and H-2d recipients when analyzed 7 wk after transfer. Taken together, these results show that in H-2b recipients, NK cells do not reject the transferred cells as 6.5+CD4−8low cells survive, but 6.5+CD4+8− cells vanish due to the lack of H-2d MHC molecules. In contrast, 6.5+CD4+8− cells survive long term in the presence of H-2d MHC molecules once not rejected by NK cells. 6.5+CD4−8low cells survived then as well.

Bottom Line: To address this issue we used recombination-activating gene (Rag)-deficient H-2b mice expressing a transgenic TCR restricted by I-Ed class II MHC molecules.After engraftment with Rag-/- H-2d fetal thymi, CD4+8- peripheral T cells emerged.Our results show that in the absence, but not in the presence, of selecting MHC molecules, peripheral mature T cells are short lived and disappear within 7 wk, indicating that continuous contact of the TCR with selecting MHC molecules is required for survival of T cells.

View Article: PubMed Central - PubMed

Affiliation: Netherlands Cancer Institute, Division of Molecular Genetics, Amsterdam.

ABSTRACT
In the thymus, T cells are selected according to their T cell receptor (TCR) specificity. After positive selection, mature cells are exported from primary lymphoid organs to seed the secondary lymphoid tissue. An important question is whether survival of mature T cells is an intrinsic property or requires continuous survival signals, i.e., engagement of the TCR by major histocompatibility complex (MHC) molecules in the periphery, perhaps in a similar way as occurring during thymic positive selection. To address this issue we used recombination-activating gene (Rag)-deficient H-2b mice expressing a transgenic TCR restricted by I-Ed class II MHC molecules. After engraftment with Rag-/- H-2d fetal thymi, CD4+8- peripheral T cells emerged. These cells were isolated and transferred into immunodeficient hosts of H-2b or H-2d haplotype, some of the latter being common cytokine receptor gamma chain deficient to exclude rejection of H-2b donor cells by host natural killer cells. Our results show that in the absence, but not in the presence, of selecting MHC molecules, peripheral mature T cells are short lived and disappear within 7 wk, indicating that continuous contact of the TCR with selecting MHC molecules is required for survival of T cells.

Show MeSH
Related in: MedlinePlus