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Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells.

Cho BK, Rao VP, Ge Q, Eisen HN, Chen J - J. Exp. Med. (2000)

Bottom Line: Thus, the homeostasis-induced memory CD8 T cells express typical memory cell markers, lyse target cells directly in vitro and in vivo, respond to lower doses of antigen than naive cells, and secrete interferon gamma faster upon restimulation.Like antigen-induced memory T cell differentiation, the homeostasis-driven process requires T cell proliferation and, initially, the presence of appropriate restricting major histocompatibility complexes, but it differs by occurring without effector cell formation and without requiring interleukin 2 or costimulation via CD28.These findings define repetitive cell division plus T cell receptor ligation as the basic requirements for naive to memory T cell differentiation.

View Article: PubMed Central - PubMed

Affiliation: Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
The developmental requirements for immunological memory, a central feature of adaptive immune responses, is largely obscure. We show that as naive CD8 T cells undergo homeostasis-driven proliferation in lymphopenic mice in the absence of overt antigenic stimulation, they progressively acquire phenotypic and functional characteristics of antigen-induced memory CD8 T cells. Thus, the homeostasis-induced memory CD8 T cells express typical memory cell markers, lyse target cells directly in vitro and in vivo, respond to lower doses of antigen than naive cells, and secrete interferon gamma faster upon restimulation. Like antigen-induced memory T cell differentiation, the homeostasis-driven process requires T cell proliferation and, initially, the presence of appropriate restricting major histocompatibility complexes, but it differs by occurring without effector cell formation and without requiring interleukin 2 or costimulation via CD28. These findings define repetitive cell division plus T cell receptor ligation as the basic requirements for naive to memory T cell differentiation.

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Requirements for homeostasis-driven proliferation. (a) Homeostasis-driven proliferation requires the presence of both “space” and the correct MHC. Proliferation of CD8+TCR+ cells in various recipients is shown as histograms of CFSE profiles. RAG-2−/− (H-2k) recipients were treated with anti-Ly49G2 (200 μg intraperitoneally) to deplete NK cells 1 d before the transfer and another 100 μg on the day of transfer. H-2k was not recognized by 2C cells as shown by mixed lymphocyte reaction (data not shown). (b) Comparison of survival of naive and memory 2C T cells in recipients with “incorrect” MHCs. An equal number of naive and memory 2C T cells (1 × 106) was transferred into either syngeneic (H-2b) RAG-1−/− recipients or RAG-2−/− recipients having an incorrect MHC class I (H-2k). 9 and 14 d after the transfer, splenocytes and lymph node cells were assayed for CD8 and TCR (1B2) expression by flow cytometry. Numbers indicate the percentages of CD8+TCR+ cells in lymph node. A similar result was also obtained in the spleen (not shown). The memory 2C T cells were generated as described in Materials and Methods and RAG-2−/− (H-2k) recipients were treated with anti-Ly49G2 antibody as above.
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Figure 6: Requirements for homeostasis-driven proliferation. (a) Homeostasis-driven proliferation requires the presence of both “space” and the correct MHC. Proliferation of CD8+TCR+ cells in various recipients is shown as histograms of CFSE profiles. RAG-2−/− (H-2k) recipients were treated with anti-Ly49G2 (200 μg intraperitoneally) to deplete NK cells 1 d before the transfer and another 100 μg on the day of transfer. H-2k was not recognized by 2C cells as shown by mixed lymphocyte reaction (data not shown). (b) Comparison of survival of naive and memory 2C T cells in recipients with “incorrect” MHCs. An equal number of naive and memory 2C T cells (1 × 106) was transferred into either syngeneic (H-2b) RAG-1−/− recipients or RAG-2−/− recipients having an incorrect MHC class I (H-2k). 9 and 14 d after the transfer, splenocytes and lymph node cells were assayed for CD8 and TCR (1B2) expression by flow cytometry. Numbers indicate the percentages of CD8+TCR+ cells in lymph node. A similar result was also obtained in the spleen (not shown). The memory 2C T cells were generated as described in Materials and Methods and RAG-2−/− (H-2k) recipients were treated with anti-Ly49G2 antibody as above.

Mentions: To examine the requirements for the homeostasis-driven T cell proliferation in our adoptive transfer system, CFSE-labeled naive 2C cells were transferred into RAG-1−/− recipients having the correct (or syngeneic) MHC haplotype (H-2b) into H-2k RAG-2−/− recipients lacking the correct MHC, or into normal (i.e., nonlymphopenic) B6 recipients having the correct MHC (H-2b). CFSE intensity, as measured by flow cytometry, revealed that the transferred T cells proliferated vigorously in the H-2b RAG-1−/− recipients but divided only minimally in the H-2b B6 recipients (Fig. 6 a), confirming that the presence of “space” is required for the proliferation. However, as early as 3 d after transfer, few surviving 2C cells were detected in H-2k RAG-2−/− recipients and by day 9, these cells could not be detected. The failure of the naive cells to survive was probably not due to destruction by NK cells because the recipients were pretreated with anti–Ly-49G2 mAb to deplete H-2b–specific NK cells. In addition, some of the transferred memory 2C cells from immunized recipients survived and remained CD44high 9 and 14 d after transfer into H-2k RAG-2−/− recipients (Fig. 6 b). Although some of the transferred memory 2C cells from nonimmunized recipients were also detected at day 9 in H-2k RAG-2−/− recipients, they were not detectable at day 14, indicating that there may be a difference in the requirement for MHC for the survival of memory cells from immunized and nonimmunized recipients. Nevertheless, our findings are consistent with various recent reports that not only the presence of “space” but also the presence of the correct MHC is required for homeostasis-driven proliferation of naive T cells 23456.


Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells.

Cho BK, Rao VP, Ge Q, Eisen HN, Chen J - J. Exp. Med. (2000)

Requirements for homeostasis-driven proliferation. (a) Homeostasis-driven proliferation requires the presence of both “space” and the correct MHC. Proliferation of CD8+TCR+ cells in various recipients is shown as histograms of CFSE profiles. RAG-2−/− (H-2k) recipients were treated with anti-Ly49G2 (200 μg intraperitoneally) to deplete NK cells 1 d before the transfer and another 100 μg on the day of transfer. H-2k was not recognized by 2C cells as shown by mixed lymphocyte reaction (data not shown). (b) Comparison of survival of naive and memory 2C T cells in recipients with “incorrect” MHCs. An equal number of naive and memory 2C T cells (1 × 106) was transferred into either syngeneic (H-2b) RAG-1−/− recipients or RAG-2−/− recipients having an incorrect MHC class I (H-2k). 9 and 14 d after the transfer, splenocytes and lymph node cells were assayed for CD8 and TCR (1B2) expression by flow cytometry. Numbers indicate the percentages of CD8+TCR+ cells in lymph node. A similar result was also obtained in the spleen (not shown). The memory 2C T cells were generated as described in Materials and Methods and RAG-2−/− (H-2k) recipients were treated with anti-Ly49G2 antibody as above.
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Figure 6: Requirements for homeostasis-driven proliferation. (a) Homeostasis-driven proliferation requires the presence of both “space” and the correct MHC. Proliferation of CD8+TCR+ cells in various recipients is shown as histograms of CFSE profiles. RAG-2−/− (H-2k) recipients were treated with anti-Ly49G2 (200 μg intraperitoneally) to deplete NK cells 1 d before the transfer and another 100 μg on the day of transfer. H-2k was not recognized by 2C cells as shown by mixed lymphocyte reaction (data not shown). (b) Comparison of survival of naive and memory 2C T cells in recipients with “incorrect” MHCs. An equal number of naive and memory 2C T cells (1 × 106) was transferred into either syngeneic (H-2b) RAG-1−/− recipients or RAG-2−/− recipients having an incorrect MHC class I (H-2k). 9 and 14 d after the transfer, splenocytes and lymph node cells were assayed for CD8 and TCR (1B2) expression by flow cytometry. Numbers indicate the percentages of CD8+TCR+ cells in lymph node. A similar result was also obtained in the spleen (not shown). The memory 2C T cells were generated as described in Materials and Methods and RAG-2−/− (H-2k) recipients were treated with anti-Ly49G2 antibody as above.
Mentions: To examine the requirements for the homeostasis-driven T cell proliferation in our adoptive transfer system, CFSE-labeled naive 2C cells were transferred into RAG-1−/− recipients having the correct (or syngeneic) MHC haplotype (H-2b) into H-2k RAG-2−/− recipients lacking the correct MHC, or into normal (i.e., nonlymphopenic) B6 recipients having the correct MHC (H-2b). CFSE intensity, as measured by flow cytometry, revealed that the transferred T cells proliferated vigorously in the H-2b RAG-1−/− recipients but divided only minimally in the H-2b B6 recipients (Fig. 6 a), confirming that the presence of “space” is required for the proliferation. However, as early as 3 d after transfer, few surviving 2C cells were detected in H-2k RAG-2−/− recipients and by day 9, these cells could not be detected. The failure of the naive cells to survive was probably not due to destruction by NK cells because the recipients were pretreated with anti–Ly-49G2 mAb to deplete H-2b–specific NK cells. In addition, some of the transferred memory 2C cells from immunized recipients survived and remained CD44high 9 and 14 d after transfer into H-2k RAG-2−/− recipients (Fig. 6 b). Although some of the transferred memory 2C cells from nonimmunized recipients were also detected at day 9 in H-2k RAG-2−/− recipients, they were not detectable at day 14, indicating that there may be a difference in the requirement for MHC for the survival of memory cells from immunized and nonimmunized recipients. Nevertheless, our findings are consistent with various recent reports that not only the presence of “space” but also the presence of the correct MHC is required for homeostasis-driven proliferation of naive T cells 23456.

Bottom Line: Thus, the homeostasis-induced memory CD8 T cells express typical memory cell markers, lyse target cells directly in vitro and in vivo, respond to lower doses of antigen than naive cells, and secrete interferon gamma faster upon restimulation.Like antigen-induced memory T cell differentiation, the homeostasis-driven process requires T cell proliferation and, initially, the presence of appropriate restricting major histocompatibility complexes, but it differs by occurring without effector cell formation and without requiring interleukin 2 or costimulation via CD28.These findings define repetitive cell division plus T cell receptor ligation as the basic requirements for naive to memory T cell differentiation.

View Article: PubMed Central - PubMed

Affiliation: Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

ABSTRACT
The developmental requirements for immunological memory, a central feature of adaptive immune responses, is largely obscure. We show that as naive CD8 T cells undergo homeostasis-driven proliferation in lymphopenic mice in the absence of overt antigenic stimulation, they progressively acquire phenotypic and functional characteristics of antigen-induced memory CD8 T cells. Thus, the homeostasis-induced memory CD8 T cells express typical memory cell markers, lyse target cells directly in vitro and in vivo, respond to lower doses of antigen than naive cells, and secrete interferon gamma faster upon restimulation. Like antigen-induced memory T cell differentiation, the homeostasis-driven process requires T cell proliferation and, initially, the presence of appropriate restricting major histocompatibility complexes, but it differs by occurring without effector cell formation and without requiring interleukin 2 or costimulation via CD28. These findings define repetitive cell division plus T cell receptor ligation as the basic requirements for naive to memory T cell differentiation.

Show MeSH
Related in: MedlinePlus