Limits...
Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells.

Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, Kim SY, Na R, Hennighausen L, Kurtulus S, Erman B, Matzinger P, Merchant MS, Mackall CL - Nat. Immunol. (2009)

Bottom Line: However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do.This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Ralpha(+) DCs.Our results indicate that IL-7Ralpha(+) DCs are regulators of the peripheral CD4(+) T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4(+) T cell population expansion in vivo.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
Interleukin 7 (IL-7) and T cell antigen receptor signals have been proposed to be the main drivers of homeostatic T cell proliferation. However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do. Here we show that systemic IL-7 concentrations increased during lymphopenia because of diminished use of IL-7 but that IL-7 signaling on IL-7 receptor-alpha-positive (IL-7Ralpha(+)) dendritic cells (DCs) in lymphopenic settings paradoxically diminished the homeostatic proliferation of CD4(+) T cells. This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Ralpha(+) DCs. Our results indicate that IL-7Ralpha(+) DCs are regulators of the peripheral CD4(+) T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4(+) T cell population expansion in vivo.

Show MeSH

Related in: MedlinePlus

BM-derived IL-7 supports, whereas stromal cell-derived IL-7 inhibits, CD4+ T cell homeostatic proliferation in lymphopenic hosts. (a,b) CFSE-labeled CD45.1+ polyclonal wild-type T cells were transferred into the indicated BM chimeras. Tx, thymectomized. (a) Representative CFSE profile measured 7 d post-transfer. (b) Numbers of CD8+CD45.1+ and CD4+CD45.1+ T cells recovered from the spleens of recipients 7 d post-transfer. CD4 (black bars) and CD8 (white bars) Data represent mean±s.e. for each group (n=6-10 mice/group) *, P<0.0001. (c,d) As in (a,b), but using CFSE-labeled Marilyn CD4+ cells (n=6-8 mice/group). *, P<0.0001. These results are representative of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2713006&req=5

Figure 3: BM-derived IL-7 supports, whereas stromal cell-derived IL-7 inhibits, CD4+ T cell homeostatic proliferation in lymphopenic hosts. (a,b) CFSE-labeled CD45.1+ polyclonal wild-type T cells were transferred into the indicated BM chimeras. Tx, thymectomized. (a) Representative CFSE profile measured 7 d post-transfer. (b) Numbers of CD8+CD45.1+ and CD4+CD45.1+ T cells recovered from the spleens of recipients 7 d post-transfer. CD4 (black bars) and CD8 (white bars) Data represent mean±s.e. for each group (n=6-10 mice/group) *, P<0.0001. (c,d) As in (a,b), but using CFSE-labeled Marilyn CD4+ cells (n=6-8 mice/group). *, P<0.0001. These results are representative of two independent experiments.

Mentions: These results and previous studies29-33 demonstrating that modulation of APC numbers induces CD4+ T cell homeostatic proliferation emphasize the influence of MHCII+ DCs on the peripheral CD4+ T cell niche. However, several studies have also implicated IL-7 as necessary for CD4+ T cell homeostatic proliferation10,34,35. To investigate whether IL-7 produced by DCs is necessary or sufficient to support CD4+ T cell homeostatic proliferation, we transferred CFSE-labeled T cells into chimeric mice engineered such that IL-7 production is limited to radioresistant stroma or radiosensitive BM-derived cells (Supplementary Fig. 5, online). Despite lymphopenia in all groups, chimeras lacking IL-7 entirely (Il7-/- BM into Il7-/- recipients) failed to support CD4+ or CD8+ T cell homeostatic proliferation. IL-7 production by both stroma and BM-derived cells (Rag1-/- BM into Rag1-/- recipients) supported substantial CD8+ but limited CD4+ T cell homeostatic proliferation. Suprisingly, absence of stromal cell-derived IL-7 in the presence of BM-derived IL-7 (Rag1-/- BM into Il7-/- recipients) resulted in massive CD4+ T cell homeostatic proliferation, whereas chimeras producing IL-7 exclusively from radioresistant stromal cells (Il7-/- BM into thymectomized wild-type recipients) failed to support CD4+ T cell homeostatic proliferation (Fig. 3b,c). To confirm that the CD4+ T cell proliferation observed was indeed homeostatic, and not antigen-driven, proliferation24, we repeated this experiment using Marilyn CD4+ cells. The results confirmed that naïve CD4+ T cells do not undergo homeostatic proliferation when IL-7 is produced by both stroma and BM-derived cells or exclusively by the stroma; however, proliferation is supported when IL-7 production is limited to the BM-derived compartment (Fig. 3d,e). Therefore, BM-derived IL-7 is sufficient to support, whereas stromal cell-derived IL-7 paradoxically diminishes, CD4+ T cell homeostatic proliferation during lymphopenia. Settings where IL-7 production is limited to BM-derived cells facilitate maximal homeostatic proliferation of CD4+ T cells.


Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells.

Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, Kim SY, Na R, Hennighausen L, Kurtulus S, Erman B, Matzinger P, Merchant MS, Mackall CL - Nat. Immunol. (2009)

BM-derived IL-7 supports, whereas stromal cell-derived IL-7 inhibits, CD4+ T cell homeostatic proliferation in lymphopenic hosts. (a,b) CFSE-labeled CD45.1+ polyclonal wild-type T cells were transferred into the indicated BM chimeras. Tx, thymectomized. (a) Representative CFSE profile measured 7 d post-transfer. (b) Numbers of CD8+CD45.1+ and CD4+CD45.1+ T cells recovered from the spleens of recipients 7 d post-transfer. CD4 (black bars) and CD8 (white bars) Data represent mean±s.e. for each group (n=6-10 mice/group) *, P<0.0001. (c,d) As in (a,b), but using CFSE-labeled Marilyn CD4+ cells (n=6-8 mice/group). *, P<0.0001. These results are representative of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2713006&req=5

Figure 3: BM-derived IL-7 supports, whereas stromal cell-derived IL-7 inhibits, CD4+ T cell homeostatic proliferation in lymphopenic hosts. (a,b) CFSE-labeled CD45.1+ polyclonal wild-type T cells were transferred into the indicated BM chimeras. Tx, thymectomized. (a) Representative CFSE profile measured 7 d post-transfer. (b) Numbers of CD8+CD45.1+ and CD4+CD45.1+ T cells recovered from the spleens of recipients 7 d post-transfer. CD4 (black bars) and CD8 (white bars) Data represent mean±s.e. for each group (n=6-10 mice/group) *, P<0.0001. (c,d) As in (a,b), but using CFSE-labeled Marilyn CD4+ cells (n=6-8 mice/group). *, P<0.0001. These results are representative of two independent experiments.
Mentions: These results and previous studies29-33 demonstrating that modulation of APC numbers induces CD4+ T cell homeostatic proliferation emphasize the influence of MHCII+ DCs on the peripheral CD4+ T cell niche. However, several studies have also implicated IL-7 as necessary for CD4+ T cell homeostatic proliferation10,34,35. To investigate whether IL-7 produced by DCs is necessary or sufficient to support CD4+ T cell homeostatic proliferation, we transferred CFSE-labeled T cells into chimeric mice engineered such that IL-7 production is limited to radioresistant stroma or radiosensitive BM-derived cells (Supplementary Fig. 5, online). Despite lymphopenia in all groups, chimeras lacking IL-7 entirely (Il7-/- BM into Il7-/- recipients) failed to support CD4+ or CD8+ T cell homeostatic proliferation. IL-7 production by both stroma and BM-derived cells (Rag1-/- BM into Rag1-/- recipients) supported substantial CD8+ but limited CD4+ T cell homeostatic proliferation. Suprisingly, absence of stromal cell-derived IL-7 in the presence of BM-derived IL-7 (Rag1-/- BM into Il7-/- recipients) resulted in massive CD4+ T cell homeostatic proliferation, whereas chimeras producing IL-7 exclusively from radioresistant stromal cells (Il7-/- BM into thymectomized wild-type recipients) failed to support CD4+ T cell homeostatic proliferation (Fig. 3b,c). To confirm that the CD4+ T cell proliferation observed was indeed homeostatic, and not antigen-driven, proliferation24, we repeated this experiment using Marilyn CD4+ cells. The results confirmed that naïve CD4+ T cells do not undergo homeostatic proliferation when IL-7 is produced by both stroma and BM-derived cells or exclusively by the stroma; however, proliferation is supported when IL-7 production is limited to the BM-derived compartment (Fig. 3d,e). Therefore, BM-derived IL-7 is sufficient to support, whereas stromal cell-derived IL-7 paradoxically diminishes, CD4+ T cell homeostatic proliferation during lymphopenia. Settings where IL-7 production is limited to BM-derived cells facilitate maximal homeostatic proliferation of CD4+ T cells.

Bottom Line: However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do.This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Ralpha(+) DCs.Our results indicate that IL-7Ralpha(+) DCs are regulators of the peripheral CD4(+) T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4(+) T cell population expansion in vivo.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
Interleukin 7 (IL-7) and T cell antigen receptor signals have been proposed to be the main drivers of homeostatic T cell proliferation. However, it is not known why CD4(+) T cells undergo less-efficient homeostatic proliferation than CD8(+) T cells do. Here we show that systemic IL-7 concentrations increased during lymphopenia because of diminished use of IL-7 but that IL-7 signaling on IL-7 receptor-alpha-positive (IL-7Ralpha(+)) dendritic cells (DCs) in lymphopenic settings paradoxically diminished the homeostatic proliferation of CD4(+) T cells. This effect was mediated at least in part by IL-7-mediated downregulation of the expression of major histocompatibility complex class II on IL-7Ralpha(+) DCs. Our results indicate that IL-7Ralpha(+) DCs are regulators of the peripheral CD4(+) T cell niche and that IL-7 signals in DCs prevent uncontrolled CD4(+) T cell population expansion in vivo.

Show MeSH
Related in: MedlinePlus