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Advantages of Foxp3(+) regulatory T cell depletion using DEREG mice.

Mayer CT, Lahl K, Milanez-Almeida P, Watts D, Dittmer U, Fyhrquist N, Huehn J, Kopf M, Kretschmer K, Rouse B, Sparwasser T - Immun Inflamm Dis (2014)

Bottom Line: Several mechanisms enable immunological self-tolerance.We here provide a detailed overview about important considerations such as DT toxicity, which affects any mouse strain treated with DT, and Treg rebound after depletion.Moreover, we discuss recent insights into the role of Tregs in viral infections.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research Feodor-Lynen-Str. 7, 30625, Hannover, Germany.

ABSTRACT
Several mechanisms enable immunological self-tolerance. Regulatory T cells (Tregs) are a specialized T cell subset that prevents autoimmunity and excessive immune responses, but can also mediate detrimental tolerance to tumors and pathogens in a Foxp3-dependent manner. Genetic tools exploiting the foxp3 locus including bacterial artificial chromosome (BAC)-transgenic DEREG mice have provided essential information on Treg biology and the potential therapeutic modulation of tolerance. In DEREG mice, Foxp3(+) Tregs selectively express eGFP and diphtheria toxin (DT) receptor, allowing for the specific depletion of Tregs through DT administration. We here provide a detailed overview about important considerations such as DT toxicity, which affects any mouse strain treated with DT, and Treg rebound after depletion. Additionally, we point out the specific advantages of BAC-transgenic DEREG mice including their suitability to study organ-specific autoimmunity such as type I diabetes. Moreover, we discuss recent insights into the role of Tregs in viral infections. In summary, DEREG mice are an important tool to study Treg-mediated tolerance and its therapeutic circumvention.

No MeSH data available.


Related in: MedlinePlus

Rapid diabetes onset upon acute Foxp3+ Treg cell ablation in NOD.DEREG mice. Normoglycemic NOD.DEREG+ females (n = 21; N = 3) were injected with DT (arrowheads). Age-matched NOD.DEREG− females were included as controls (n = 6; N = 1). Pooled percentages of normoglycemic mice are shown over time (***p < 0.001, Log-rank and Gehan–Breslow–Wilcoxon tests).
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fig02: Rapid diabetes onset upon acute Foxp3+ Treg cell ablation in NOD.DEREG mice. Normoglycemic NOD.DEREG+ females (n = 21; N = 3) were injected with DT (arrowheads). Age-matched NOD.DEREG− females were included as controls (n = 6; N = 1). Pooled percentages of normoglycemic mice are shown over time (***p < 0.001, Log-rank and Gehan–Breslow–Wilcoxon tests).

Mentions: We have previously described that eGFP−Foxp3+ Tregs can be selected by long-term DT treatment or by certain infections combined with DT treatment of DEREG mice [12,15,16]. Similar observations were made with Foxp3.LuciDTR mice undergoing prolonged DT treatment [3]. The existence of DT-resistant Tregs has provided important insights into Treg homeostasis and self-tolerance [3,17]. Additionally, adult DEREG mice are protected from lethal autoimmunity as opposed to Foxp3DTR knock-in mice due to DT-resistant Tregs [1,2,17]. This important advantage allows studying the specific effects of transient Treg depletion. For example, the DEREG transgene is particularly suited to study organ-specific autoimmunity in mice on genetically susceptible backgrounds. We have crossed DEREG mice on the NOD background as a model of human type I diabetes. Interestingly, 70% of non-diabetic NOD.DEREG mice develop overt diabetes after Treg depletion, whereas DT-treated NOD controls remain non-diabetic (Fig. 2). Thus, Foxp3+ Tregs maintain self-tolerance to insulin-producing beta cells in the absence of TCR transgenes. Independent of Treg depletion, the Foxp3 BAC-encoded eGFP in DEREG mice has been instrumental in Treg isolation and functional analyses [18]. This is particularly important to mention because Foxp3 modifications in knock-in strains can alter Treg functions [17]. In contrast, Foxp3 maintains its native state in DEREG mice.


Advantages of Foxp3(+) regulatory T cell depletion using DEREG mice.

Mayer CT, Lahl K, Milanez-Almeida P, Watts D, Dittmer U, Fyhrquist N, Huehn J, Kopf M, Kretschmer K, Rouse B, Sparwasser T - Immun Inflamm Dis (2014)

Rapid diabetes onset upon acute Foxp3+ Treg cell ablation in NOD.DEREG mice. Normoglycemic NOD.DEREG+ females (n = 21; N = 3) were injected with DT (arrowheads). Age-matched NOD.DEREG− females were included as controls (n = 6; N = 1). Pooled percentages of normoglycemic mice are shown over time (***p < 0.001, Log-rank and Gehan–Breslow–Wilcoxon tests).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257761&req=5

fig02: Rapid diabetes onset upon acute Foxp3+ Treg cell ablation in NOD.DEREG mice. Normoglycemic NOD.DEREG+ females (n = 21; N = 3) were injected with DT (arrowheads). Age-matched NOD.DEREG− females were included as controls (n = 6; N = 1). Pooled percentages of normoglycemic mice are shown over time (***p < 0.001, Log-rank and Gehan–Breslow–Wilcoxon tests).
Mentions: We have previously described that eGFP−Foxp3+ Tregs can be selected by long-term DT treatment or by certain infections combined with DT treatment of DEREG mice [12,15,16]. Similar observations were made with Foxp3.LuciDTR mice undergoing prolonged DT treatment [3]. The existence of DT-resistant Tregs has provided important insights into Treg homeostasis and self-tolerance [3,17]. Additionally, adult DEREG mice are protected from lethal autoimmunity as opposed to Foxp3DTR knock-in mice due to DT-resistant Tregs [1,2,17]. This important advantage allows studying the specific effects of transient Treg depletion. For example, the DEREG transgene is particularly suited to study organ-specific autoimmunity in mice on genetically susceptible backgrounds. We have crossed DEREG mice on the NOD background as a model of human type I diabetes. Interestingly, 70% of non-diabetic NOD.DEREG mice develop overt diabetes after Treg depletion, whereas DT-treated NOD controls remain non-diabetic (Fig. 2). Thus, Foxp3+ Tregs maintain self-tolerance to insulin-producing beta cells in the absence of TCR transgenes. Independent of Treg depletion, the Foxp3 BAC-encoded eGFP in DEREG mice has been instrumental in Treg isolation and functional analyses [18]. This is particularly important to mention because Foxp3 modifications in knock-in strains can alter Treg functions [17]. In contrast, Foxp3 maintains its native state in DEREG mice.

Bottom Line: Several mechanisms enable immunological self-tolerance.We here provide a detailed overview about important considerations such as DT toxicity, which affects any mouse strain treated with DT, and Treg rebound after depletion.Moreover, we discuss recent insights into the role of Tregs in viral infections.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover and the Helmholtz Centre for Infection Research Feodor-Lynen-Str. 7, 30625, Hannover, Germany.

ABSTRACT
Several mechanisms enable immunological self-tolerance. Regulatory T cells (Tregs) are a specialized T cell subset that prevents autoimmunity and excessive immune responses, but can also mediate detrimental tolerance to tumors and pathogens in a Foxp3-dependent manner. Genetic tools exploiting the foxp3 locus including bacterial artificial chromosome (BAC)-transgenic DEREG mice have provided essential information on Treg biology and the potential therapeutic modulation of tolerance. In DEREG mice, Foxp3(+) Tregs selectively express eGFP and diphtheria toxin (DT) receptor, allowing for the specific depletion of Tregs through DT administration. We here provide a detailed overview about important considerations such as DT toxicity, which affects any mouse strain treated with DT, and Treg rebound after depletion. Additionally, we point out the specific advantages of BAC-transgenic DEREG mice including their suitability to study organ-specific autoimmunity such as type I diabetes. Moreover, we discuss recent insights into the role of Tregs in viral infections. In summary, DEREG mice are an important tool to study Treg-mediated tolerance and its therapeutic circumvention.

No MeSH data available.


Related in: MedlinePlus