Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Nov;51 Suppl 4(0 4):160S-168S.
doi: 10.1111/j.1537-2995.2011.03379.x.

Cellular therapies supplement: the role of granulocyte macrophage colony-stimulating factor and dendritic cells in regulatory T-cell homeostasis and expansion

Tao Zou  1 , Atsushi Satake, Priti Ojha, Taku Kambayashi
Affiliations

Cellular therapies supplement: the role of granulocyte macrophage colony-stimulating factor and dendritic cells in regulatory T-cell homeostasis and expansion

Tao Zou et al. Transfusion. 2011 Nov.

Abstract

Regulatory T cells are a subset of T cells with inhibitory function that are critical for protection against autoimmunity and immunopathology. A failure to maintain adequate regulatory T-cell numbers in the periphery results in autoimmune manifestations, highlighting the importance of the continuous maintenance of peripheral regulatory T cells. The cellular and molecular requirements for regulatory T-cell homeostasis and expansion are not fully understood but involve a complex interplay among dendritic cells, conventional T cells, and regulatory T cells. In addition, soluble factors such as the cytokine granulocyte macrophage colony-stimulating factor may play a role in enhancing these interactions. In this review, we discuss our National Blood Foundation-funded studies relating to the role of granulocyte macrophage colony-stimulating factor and dendritic cells in controlling regulatory T-cell homeostasis and expansion.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest: None

Figures

Figure 1
Figure 1. Co-culture of Balb/c splenocytes with C57BL/6-derived mast cells promotes Treg proliferation
Single cell suspensions from spleens of Balb/c mice were CFSE-labeled and incubated with or without C57BL/6 bone marrow-derived mast cells with IL-3 for 4 days. T cell proliferation was measured by analyzing CFSE-diluted cells by flow cytometry. The plots are gated on Tregs (CD4+FoxP3+; top plots) or Tconvs (CD4+FoxP3−; bottom plots). The number in the each plot represents the % of divided (CFSE-diluted) cells.
Figure 2
Figure 2. IL-3, IL-5, and GMCSF selectively induce Treg proliferation in vitro
Single cell suspensions from spleens of Balb/c mice were CFSE-labeled and incubated without (left) or with IL-3 (10ng/ml; 2nd left), IL-5 (10ng/ml; 2nd right), or GMCSF (10ng/ml; right) for 4 days. T cell proliferation was measured by analyzing CFSE-diluted cells by flow cytometry. The plots are gated on Tregs (CD4+FoxP3+; top plots) or Tconvs (CD4+FoxP3−; bottom plots). The number in the each plot represents the % of divided (CFSE-diluted) cells.
Figure 3
Figure 3. Expansion of DCs in vivo causes increased Treg proliferation
CD11c-DTR mice (transgenic mice with diphtheria toxin receptor expression driven by the CD11c promoter) were injected subcutaneously with B16 or B16-FLT3L tumor cells and nine days later administered BrdU for three days. DC depletion was performed by daily diphtheria toxin administration started 2 days before BrdU treatment. BrdU incorporation of splenic Tregs from these mice was measured by flow cytometry. The graphs show BrdU incorporation by Tregs (CD4+FoxP3+ cells).
Figure 4
Figure 4. Blockade of CD80, CD86, and OX40L inhibits IL-2-induced Treg proliferation in vitro
FACS-sorted CFSE-labeled C57BL/6 Tregs (CD4+CD25+) were co-cultured with purified MHC class II-deficient DCs (CD11c+) and IL-2 with or without CTLA4Ig, αOX40L, αCD40L, or all 3 antibodies combined each at 20 µg/ml for 4d ays. CFSE dilution was analyzed in CD4+FoxP3+ Tregs by flow cytometry. Plots are gated on live CD4+FoxP3+ cells and the number in the each plot represents the % of divided (CFSE-diluted) cells.
Figure 5
Figure 5. Interactions among DCs, Tconvs, and Tregs are necessary for Treg proliferation
Tconvs are induced to produce IL-2 upon interaction with syngeneic DCs in an MHC class II/TCR and co-stimulatory molecule-dependent manner. This IL-2 in turn binds to the IL-2 receptor (IL-2R) on Tregs and induces their proliferation. IL-2-induced Treg proliferation requires contact with DCs but can occur in an MHC class II– dependent and –independent manner. Co-stimulatory molecules play an important role in the MHC-independent mode of Treg proliferation. The cytokines IL-3 and GMCSF facilitate this process by upregulating MHC class II and co-stimulatory molecule expression by DCs.
Figure 6
Figure 6. IL-3β−/−βc−/− mice contain fewer Treg compared to wildtype mice
The spleen, inguinal lymph nodes, and mesenteric lymph nodes of C57BL/6 and IL-3β−/−βc−/− mice were harvested and analyzed for CD4+FoxP3+ T cells. Using wildtype mice as baseline, the % decrease in FoxP3+ T cells among total CD4+ T cells from IL-3β−/−βc−/− mice was determined. Results are expressed as mean ± SD of N = 4 mice/group.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987;49:273–280. - PubMed
    1. Kisielow P, Bluthmann H, Staerz UD, et al. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988;333:742–746. - PubMed
    1. Liston A, Rudensky AY. Thymic development and peripheral homeostasis of regulatory T cells Curr Opin Immunol. 2007:176–185. - PubMed
    1. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–336. - PubMed
    1. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25) Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases J Immunol. 1995:1151–1164. - PubMed

Publication types

MeSH terms

Substances