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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.

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Elevated systemic IL-7 preferentially expands CD8+ but not CD4+ T cells. (a,b) CD45.1+ LN T cells were labeled with CFSE and transferred into CD45.2+ wild-type (WT) or Rag1-/- recipients. (a) CFSE dilution was analyzed 7 d later. Representative CFSE profile. (b) Numbers of CD8+CD45.1+ and CD4+CD45.1+ T cells recovered from the spleens of recipients 7 d post-transfer (n=6-8 mice per group). (c) As in (a), but using CFSE-labeled Marilyn CD4+ cells. Results are representative of three independent experiments. (d,e) Polyclonal CD45.1+ LN T cells were labeled with CFSE and transferred into CD45.2+ wild-type recipients treated with PBS or IL-7 (10μg/day). (d) CFSE dilution was analyzed 7 d post-transfer. Representative CFSE profile. (e) Numbers of CD45.1+CD8+ and CD45.1+CD4+ T cells recovered from the spleens of recipient mice (n=3-6 mice/group) (f) As in (d), but using CFSE-labeled Marilyn CD4+ cells. These results are representative of four independent experiments.
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Figure 2: Elevated systemic IL-7 preferentially expands CD8+ but not CD4+ T cells. (a,b) CD45.1+ LN T cells were labeled with CFSE and transferred into CD45.2+ wild-type (WT) or Rag1-/- recipients. (a) CFSE dilution was analyzed 7 d later. Representative CFSE profile. (b) Numbers of CD8+CD45.1+ and CD4+CD45.1+ T cells recovered from the spleens of recipients 7 d post-transfer (n=6-8 mice per group). (c) As in (a), but using CFSE-labeled Marilyn CD4+ cells. Results are representative of three independent experiments. (d,e) Polyclonal CD45.1+ LN T cells were labeled with CFSE and transferred into CD45.2+ wild-type recipients treated with PBS or IL-7 (10μg/day). (d) CFSE dilution was analyzed 7 d post-transfer. Representative CFSE profile. (e) Numbers of CD45.1+CD8+ and CD45.1+CD4+ T cells recovered from the spleens of recipient mice (n=3-6 mice/group) (f) As in (d), but using CFSE-labeled Marilyn CD4+ cells. These results are representative of four independent experiments.

Mentions: To compare the capacity for lymphopenia to drive homeostatic proliferation of CD4+ versus CD8+ T cell populations, lymph node (LN)-derived T cells were labeled with CFSE and transferred into Rag1-/- recipients. Within seven days, most CD8+ T cells proliferated, but the majority of CD4+ T cells did not divide (Fig. 2a,b). As reported previously, proliferation of polyclonal CD4+ populations in Rag1-/- mice was limited to a subset of rapidly dividing cells, which have been described as IL-7-independent, cross-reactive with environmental antigens and likely derived from memory CD4+ T cells23,24. Consistent with this hypothesis, we detected minimal proliferation of polyclonal CD4+ T cell populations depleted of CD44hi cells in Rag1-/- mice (Supplementary Fig. 2, online). Similarly, an exclusively naïve CD4+ population comprised of T cells from TCR transgenic `Marilyn' mice, which bear a single TCR restricted for MHCII in association with Dby, an antigen contained in the male HY complex, did not proliferate in female Rag1-/- mice; this finding agrees with previous findings using CD4+ T cells bearing other TCR transgenes25,26 (Fig. 2c). Therefore, lymphopenia efficiently supports homeostatic proliferation of bulk CD8+ but not CD4+ T cells, and induces essentially no proliferation of naïve CD4+ 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)

Elevated systemic IL-7 preferentially expands CD8+ but not CD4+ T cells. (a,b) CD45.1+ LN T cells were labeled with CFSE and transferred into CD45.2+ wild-type (WT) or Rag1-/- recipients. (a) CFSE dilution was analyzed 7 d later. Representative CFSE profile. (b) Numbers of CD8+CD45.1+ and CD4+CD45.1+ T cells recovered from the spleens of recipients 7 d post-transfer (n=6-8 mice per group). (c) As in (a), but using CFSE-labeled Marilyn CD4+ cells. Results are representative of three independent experiments. (d,e) Polyclonal CD45.1+ LN T cells were labeled with CFSE and transferred into CD45.2+ wild-type recipients treated with PBS or IL-7 (10μg/day). (d) CFSE dilution was analyzed 7 d post-transfer. Representative CFSE profile. (e) Numbers of CD45.1+CD8+ and CD45.1+CD4+ T cells recovered from the spleens of recipient mice (n=3-6 mice/group) (f) As in (d), but using CFSE-labeled Marilyn CD4+ cells. These results are representative of four independent experiments.
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Related In: Results  -  Collection

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Figure 2: Elevated systemic IL-7 preferentially expands CD8+ but not CD4+ T cells. (a,b) CD45.1+ LN T cells were labeled with CFSE and transferred into CD45.2+ wild-type (WT) or Rag1-/- recipients. (a) CFSE dilution was analyzed 7 d later. Representative CFSE profile. (b) Numbers of CD8+CD45.1+ and CD4+CD45.1+ T cells recovered from the spleens of recipients 7 d post-transfer (n=6-8 mice per group). (c) As in (a), but using CFSE-labeled Marilyn CD4+ cells. Results are representative of three independent experiments. (d,e) Polyclonal CD45.1+ LN T cells were labeled with CFSE and transferred into CD45.2+ wild-type recipients treated with PBS or IL-7 (10μg/day). (d) CFSE dilution was analyzed 7 d post-transfer. Representative CFSE profile. (e) Numbers of CD45.1+CD8+ and CD45.1+CD4+ T cells recovered from the spleens of recipient mice (n=3-6 mice/group) (f) As in (d), but using CFSE-labeled Marilyn CD4+ cells. These results are representative of four independent experiments.
Mentions: To compare the capacity for lymphopenia to drive homeostatic proliferation of CD4+ versus CD8+ T cell populations, lymph node (LN)-derived T cells were labeled with CFSE and transferred into Rag1-/- recipients. Within seven days, most CD8+ T cells proliferated, but the majority of CD4+ T cells did not divide (Fig. 2a,b). As reported previously, proliferation of polyclonal CD4+ populations in Rag1-/- mice was limited to a subset of rapidly dividing cells, which have been described as IL-7-independent, cross-reactive with environmental antigens and likely derived from memory CD4+ T cells23,24. Consistent with this hypothesis, we detected minimal proliferation of polyclonal CD4+ T cell populations depleted of CD44hi cells in Rag1-/- mice (Supplementary Fig. 2, online). Similarly, an exclusively naïve CD4+ population comprised of T cells from TCR transgenic `Marilyn' mice, which bear a single TCR restricted for MHCII in association with Dby, an antigen contained in the male HY complex, did not proliferate in female Rag1-/- mice; this finding agrees with previous findings using CD4+ T cells bearing other TCR transgenes25,26 (Fig. 2c). Therefore, lymphopenia efficiently supports homeostatic proliferation of bulk CD8+ but not CD4+ T cells, and induces essentially no proliferation of naïve CD4+ 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