Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells - PubMed (original) (raw)
. 2004 Feb 2;199(3):303-13.
doi: 10.1084/jem.20031562.
Kerstin Siegmund, Joachim C U Lehmann, Christiane Siewert, Uta Haubold, Markus Feuerer, Gudrun F Debes, Joerg Lauber, Oliver Frey, Grzegorz K Przybylski, Uwe Niesner, Maurus de la Rosa, Christian A Schmidt, Rolf Bräuer, Jan Buer, Alexander Scheffold, Alf Hamann
Affiliations
- PMID: 14757740
- PMCID: PMC2211798
- DOI: 10.1084/jem.20031562
Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells
Jochen Huehn et al. J Exp Med. 2004.
Abstract
Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin alphaEbeta7 discriminates distinct subsets of murine CD4+ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. alphaE-CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, alphaE -positive subsets (CD25+ and CD25-) displayed an effector/memory phenotype expressing high levels of E/P-selectin-binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, alphaE -expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.
Figures
Figure 1.
Foxp3 expression in Treg subsets. Foxp3 mRNA expression was determined in sorted Treg subsets by real-time quantitative RT-PCR. Obtained values were normalized to the housekeeping gene hypoxanthine phosphoribosyltransferase and expressed as percentage of the level found in CD25 single positive cells (mean ± SD of three independent experiments).
Figure 2.
Phenotyping for effector/memory markers as well as adhesion molecules unravels a high degree of heterogeneity among Treg subsets. FACS® analysis of pooled spleen and lymph node cells shows the expression of several effector/memory markers and adhesion molecules on indicated CD4+ T cell subsets. Representative histogram plots from three independent experiments were selected showing stainings (gray) plus isotype controls (white). The graphs summarize data from one representative experiment and show frequency or mean fluorescence intensity of the indicated subsets as mean ± SD from three independently analyzed animals.
Figure 3.
αE-expressing Treg subsets have undergone excessive proliferation. Sorted Treg subsets from pooled spleen and lymph node cells were analyzed for their TREC content. Shown is the TREC number per 1,000 cells of the indicated subsets as mean ± SD of three parallel samples from one representative out of six independent measurements. Significance (*, P < 0.05) was computed from the six means. The average TREC number per 1,000 cells in CD4+CD8− thymocytes (“high control”) and cultured Th1 cells (“low control”) was 80 and 1, respectively (not depicted).
Figure 4.
αE-expressing subsets have a higher migratory capacity toward inflammatory chemokines. The chemotactic response of pooled spleen and lymph node T cells to 30 nM CCL19, 100 nM CXCL9, 100 nM CCL17, and 10 nM CCL20 was analyzed in an in vitro chemotaxis assay. The number of migrating cells of each subset was measured by flow cytometry. Results are expressed as the percentage of the indicated subset that migrated to the lower chamber and where normalized to the mean migration rate of all subsets. Shown is the mean ± SD of three (CCL17, CCL20) or four (CCL19, CXCL9) experiments (*, P < 0.05; **, P < 0.01). Basal migration toward medium alone (dotted lines) showed no significant differences between the subsets.
Figure 5.
CD25 single positive cells display a stronger migration into lymph nodes, but αE single positive cells can efficiently enter inflamed sites. (A) Radioactively labeled T cell subsets were injected i.v. into naive Balb/c mice followed by the determination of radioactivity in the indicated organs after 24 h using a γ-counter. Percentage of total recovered radioactivity is shown (n = 4; mean ± SD; one representative out of two independent experiments). (B) Radioactively labeled T cell subsets were injected i.v. in Balb/c mice that had been sensitized and challenged with DNFB. Recovered radioactivity from control and inflamed ear pinna was determined after 24 h (n = 6; mean ± SD; *, P < 0.05; **, P < 0.01).
Figure 6.
αE-expressing subsets show the strongest suppression of inflammatory reactions in antigen-induced arthritis. (A and B) mBSA-immunized C57Bl6 mice received 105 FACS®-sorted and polyclonally preactivated cells 24 h before intraarticular mBSA injection (αE +CD25+, n = 4; αE +CD25−, n = 4; αE −CD25+, n = 11; αE −CD25−, n = 11; and PBS alone, n = 10). (A) The progression of arthritis was monitored by the measurement of knee joint swelling (mean ± SD; one representative out of two independent experiments). αE +CD25+ and αE +CD25− cells showed a higher suppressive capacity than CD25 single positive cells (P < 0.01 and P = 0.085, respectively). (B) At day 14, tissues were taken for histological examination. The final arthritis score was evaluated for each animal (mean ± SEM; one representative out of two independent experiments). αE +CD25+ cells showed a significantly lower arthritis score than CD25 single positive cells (*, P < 0.05). (C) Radioactively labeled T cell subsets were injected i.v. in mBSA-immunized mice that had received an intraarticular mBSA injection 4 d before the homing experiment. Recovered radioactivity from the inflamed knee was determined after 24 h using a γ-counter. Percentage of total recovered radioactivity is shown (n = 6; mean ± SD; one representative out of two independent experiments). αE +CD25+ and αE +CD25− cells showed a significantly higher migration into the inflamed knee joint compared with CD25 single positive cells (*, P < 0.05).
Figure 7.
CD25 single positive cells represent natural Tregs, whereas αE-expressing subsets are prototypes of adaptive Tregs.
Similar articles
- Experience-driven development: effector/memory-like alphaE+Foxp3+ regulatory T cells originate from both naive T cells and naturally occurring naive-like regulatory T cells.
Siewert C, Lauer U, Cording S, Bopp T, Schmitt E, Hamann A, Huehn J. Siewert C, et al. J Immunol. 2008 Jan 1;180(1):146-55. doi: 10.4049/jimmunol.180.1.146. J Immunol. 2008. PMID: 18097014 - The migratory behavior of murine CD4+ cells of memory phenotype.
Tietz W, Hamann A. Tietz W, et al. Eur J Immunol. 1997 Sep;27(9):2225-32. doi: 10.1002/eji.1830270916. Eur J Immunol. 1997. PMID: 9341763 - Suppression of CD4+ T lymphocyte effector functions by CD4+CD25+ cells in vivo.
Martin B, Banz A, Bienvenu B, Cordier C, Dautigny N, Bécourt C, Lucas B. Martin B, et al. J Immunol. 2004 Mar 15;172(6):3391-8. doi: 10.4049/jimmunol.172.6.3391. J Immunol. 2004. PMID: 15004137 - Migration rules: functional properties of naive and effector/memory-like regulatory T cell subsets.
Huehn J, Siegmund K, Hamann A. Huehn J, et al. Curr Top Microbiol Immunol. 2005;293:89-114. doi: 10.1007/3-540-27702-1_5. Curr Top Microbiol Immunol. 2005. PMID: 15981477 Review. - Thymic commitment of regulatory T cells is a pathway of TCR-dependent selection that isolates repertoires undergoing positive or negative selection.
Coutinho A, Caramalho I, Seixas E, Demengeot J. Coutinho A, et al. Curr Top Microbiol Immunol. 2005;293:43-71. doi: 10.1007/3-540-27702-1_3. Curr Top Microbiol Immunol. 2005. PMID: 15981475 Review.
Cited by
- Phenotypic profiling of human induced regulatory T cells at early differentiation: insights into distinct immunosuppressive potential.
Kattelus R, Starskaia I, Lindén M, Batkulwar K, Pietilä S, Moulder R, Marson A, Rasool O, Suomi T, Elo LL, Lahesmaa R, Buchacher T. Kattelus R, et al. Cell Mol Life Sci. 2024 Sep 12;81(1):399. doi: 10.1007/s00018-024-05429-3. Cell Mol Life Sci. 2024. PMID: 39264416 Free PMC article. - Deciphering the developmental trajectory of tissue-resident Foxp3+ regulatory T cells.
Alvarez F, Liu Z, Bay A, Piccirillo CA. Alvarez F, et al. Front Immunol. 2024 Mar 28;15:1331846. doi: 10.3389/fimmu.2024.1331846. eCollection 2024. Front Immunol. 2024. PMID: 38605970 Free PMC article. Review. - Renal graft function in transplanted patients correlates with CD45RC T cell phenotypic signature.
Bézie S, Sérazin C, Autrusseau E, Vimond N, Giral M, Anegon I, Guillonneau C. Bézie S, et al. PLoS One. 2024 Mar 21;19(3):e0300032. doi: 10.1371/journal.pone.0300032. eCollection 2024. PLoS One. 2024. PMID: 38512889 Free PMC article. - Beyond FOXP3: a 20-year journey unravelling human regulatory T-cell heterogeneity.
Santosh Nirmala S, Kayani K, Gliwiński M, Hu Y, Iwaszkiewicz-Grześ D, Piotrowska-Mieczkowska M, Sakowska J, Tomaszewicz M, Marín Morales JM, Lakshmi K, Marek-Trzonkowska NM, Trzonkowski P, Oo YH, Fuchs A. Santosh Nirmala S, et al. Front Immunol. 2024 Jan 12;14:1321228. doi: 10.3389/fimmu.2023.1321228. eCollection 2023. Front Immunol. 2024. PMID: 38283365 Free PMC article. Review. - Age-Dependent Effect of Calcitriol on Mouse Regulatory T and B Lymphocytes.
Śnieżewska A, Anisiewicz A, Gdesz-Birula K, Wietrzyk J, Filip-Psurska B. Śnieżewska A, et al. Nutrients. 2023 Dec 22;16(1):49. doi: 10.3390/nu16010049. Nutrients. 2023. PMID: 38201878 Free PMC article.
References
- Shevach, E.M. 2002. CD4+ CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2:389–400. - PubMed
- Hori, S., T. Nomura, and S. Sakaguchi. 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science. 299:1057–1061. - PubMed
- Itoh, M., T. Takahashi, N. Sakaguchi, Y. Kuniyasu, J. Shimizu, F. Otsuka, and S. Sakaguchi. 1999. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162:5317–5326. - PubMed
- Papiernik, M., M.L. de Moraes, C. Pontoux, F. Vasseur, and C. Penit. 1998. Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int. Immunol. 10:371–378. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials