IL-4-IRES-eGFP (4get) Reporter Mice: Monitor Polarized Immune Response
Applications: Immunology, inflammation, and oncology
The reliable monitoring and sorting of IL-4-secreting cells enables you to efficiently delineate the immune response polarization toward the Th2 pathway, and therefore represents a powerful drug testing tool to:
- Modulate chronic inflammation caused by tissue-resident macrophages
- Study airway inflammation related to allergic asthma
Model features:
- Physiological expression of IL-4
- eGFP reporter faithfully mirrors IL-4 expression
References
This IL-4 reporter mouse model is widely used and validated, with more than 60 publications available from independent renowned laboratories.
Original reference:
Mohrs M; Shinkai K; Mohrs K; Locksley RM. 2001. Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter. Immunity 15(2):303-11. [PubMed]
Additional References
2011
Sofi MH; Qiao Y; Ansel KM; Kubo M; Chang CH. 2011. Induction and Maintenance of IL-4 Expression Are Regulated Differently by the 3' Enhancer in CD4 T Cells. J Immunol 186(5):2792-9. [PubMed]
Wu D; Molofsky AB; Liang HE; Ricardo-Gonzalez RR; Jouihan HA; Bando JK; Chawla A; Locksley RM. 2011. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332(6026):243-7. [PubMed]
2010
Cheng LE; Wang ZE; Locksley RM. 2010. Murine B cells regulate serum IgE levels in a CD23-dependent manner. J Immunol 185(9):5040-7. [PubMed]
Girtsman T; Jaffar Z; Ferrini M; Shaw P; Roberts K. 2010. Natural Foxp3(+) regulatory T cells inhibit Th2 polarization but are biased toward suppression of Th17-driven lung inflammation. J Leukoc Biol 88(3):537-46. [PubMed]
Hammad H; Plantinga M; Deswarte K; Pouliot P; Willart MA; Kool M; Muskens F; Lambrecht BN. 2010. Inflammatory dendritic cells--not basophils--are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J Exp Med 207(10):2097-111. [PubMed]
Huber S; Hoffmann R; Muskens F; Voehringer D. 2010. Alternatively activated macrophages inhibit T-cell proliferation by Stat6-dependent expression of PD-L2. Blood 116(17):3311-20. [PubMed]
Jang S; Schaller M; Berlin AA; Lukacs NW. 2010. Notch Ligand Delta-Like 4 Regulates Development and Pathogenesis of Allergic Airway Responses by Modulating IL-2 Production and Th2 Immunity. J Immunol 185(10):5835-44. [PubMed]
Oboki K; Ohno T; Kajiwara N; Arae K; Morita H; Ishii A; Nambu A; Abe T; Kiyonari H; Matsumoto K; Sudo K; Okumura K; Saito H; Nakae S. 2010. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci U S A 107(43):18581-6. [PubMed]
Ohnmacht C; Schwartz C; Panzer M; Schiedewitz I; Naumann R; Voehringer D. 2010. Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 33(3):364-74. [PubMed]
Perona-Wright G; Mohrs K; Mayer KD; Mohrs M. 2010. Differential regulation of IL-4Ralpha expression by antigen versus cytokine stimulation characterizes Th2 progression in vivo. J Immunol 184(2):615-23. [PubMed]
Perona-Wright G; Mohrs K; Mohrs M. 2010. Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node. Nat Immunol 11(6):520-6. [PubMed]
Price AE; Liang HE; Sullivan BM; Reinhardt RL; Eisley CJ; Erle DJ; Locksley RM. 2010. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A 107(25):11489-94. [PubMed]
Tang H; Cao W; Kasturi SP; Ravindran R; Nakaya HI; Kundu K; Murthy N; Kepler TB; Malissen B; Pulendran B. 2010. The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling. Nat Immunol 11(7):608-17. [PubMed]
Wang Y; Souabni A; Flavell RA; Wan YY. 2010. An intrinsic mechanism predisposes foxp3-expressing regulatory T cells to th2 conversion in vivo. J Immunol 185(10):5983-92. [PubMed]
2009
Clay BS; Shilling RA; Bandukwala HS; Moore TV; Cannon JL; Welcher AA; Weinstock JV; Sperling AI. 2009. Inducible costimulator expression regulates the magnitude of Th2-mediated airway inflammation by regulating the number of Th2 cells. PLoS One 4(11):e7525. [PubMed]
Dolgachev V; Petersen BC; Budelsky AL; Berlin AA; Lukacs NW. 2009. Pulmonary IL-17E (IL-25) production and IL-17RB+ myeloid cell-derived Th2 cytokine production are dependent upon stem cell factor-induced responses during chronic allergic pulmonary disease. J Immunol 183(9):5705-15. [PubMed]
Everts B; Perona-Wright G; Smits HH; Hokke CH; van der Ham AJ; Fitzsimmons CM; Doenhoff MJ; van der Bosch J; Mohrs K; Haas H; Mohrs M; Yazdanbakhsh M; Schramm G. 2009. Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses. J Exp Med 206(8):1673-80. [PubMed]
Fukuyama T; Kasper LH; Boussouar F; Jeevan T; van Deursen J; Brindle PK. 2009. Histone acetyltransferase CBP is vital to demarcate conventional and innate CD8+ T-cell development. Mol Cell Biol 29(14):3894-904. [PubMed]
King IL; Mohrs M. 2009. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med 206(5):1001-7. [PubMed]
McKee AS; Munks MW; MacLeod MK; Fleenor CJ; Van Rooijen N; Kappler JW; Marrack P. 2009. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol 183(7):4403-14. [PubMed]
Mingueneau M; Roncagalli R; Gregoire C; Kissenpfennig A; Miazek A; Archambaud C; Wang Y; Perrin P; Bertosio E; Sansoni A; Richelme S; Locksley RM; Aguado E; Malissen M; Malissen B. 2009. Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor. Immunity 31(2):197-208. [PubMed]
Moore ML; Newcomb DC; Parekh VV; Van Kaer L; Collins RD; Zhou W; Goleniewska K; Chi MH; Mitchell D; Boyce JA; Durbin JE; Sturkie C; Peebles RS Jr. 2009. STAT1 negatively regulates lung basophil IL-4 expression induced by respiratory syncytial virus infection. J Immunol 183(3):2016-26. [PubMed]
Ohnmacht C; Voehringer D. 2009. Basophil effector function and homeostasis during helminth infection. Blood 113(12):2816-25. [PubMed]
Rangel-Moreno J; Moyron-Quiroz JE; Carragher DM; Kusser K; Hartson L; Moquin A; Randall TD. 2009. Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity 30(5):731-43. [PubMed]
Reinhardt RL; Liang HE; Locksley RM. 2009. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol 10(4):385-93. [PubMed]
Sokol CL; Chu NQ; Yu S; Nish SA; Laufer TM; Medzhitov R. 2009. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol 10(7):713-20. [PubMed]
Wojciechowski W; Harris DP; Sprague F; Mousseau B; Makris M; Kusser K; Honjo T; Mohrs K; Mohrs M; Randall T; Lund FE. 2009. Cytokine-producing effector B cells regulate type 2 immunity to H. polygyrus. Immunity 30(3):421-33. [PubMed]
Yang XO; Angkasekwinai P; Zhu J; Peng J; Liu Z; Nurieva R; Liu X; Chung Y; Chang SH; Sun B; Dong C. 2009. Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat Immunol 10(12):1260-6. [PubMed]
Zaretsky AG; Taylor JJ; King IL; Marshall FA; Mohrs M; Pearce EJ. 2009. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 206(5):991-9. [PubMed]
Sofi MH; Qiao Y; Ansel KM; Kubo M; Chang CH. 2011. Induction and Maintenance of IL-4 Expression Are Regulated Differently by the 3' Enhancer in CD4 T Cells. J Immunol 186(5):2792-9. [PubMed]
Wu D; Molofsky AB; Liang HE; Ricardo-Gonzalez RR; Jouihan HA; Bando JK; Chawla A; Locksley RM. 2011. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332(6026):243-7. [PubMed]
2010
Cheng LE; Wang ZE; Locksley RM. 2010. Murine B cells regulate serum IgE levels in a CD23-dependent manner. J Immunol 185(9):5040-7. [PubMed]
Girtsman T; Jaffar Z; Ferrini M; Shaw P; Roberts K. 2010. Natural Foxp3(+) regulatory T cells inhibit Th2 polarization but are biased toward suppression of Th17-driven lung inflammation. J Leukoc Biol 88(3):537-46. [PubMed]
Hammad H; Plantinga M; Deswarte K; Pouliot P; Willart MA; Kool M; Muskens F; Lambrecht BN. 2010. Inflammatory dendritic cells--not basophils--are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J Exp Med 207(10):2097-111. [PubMed]
Huber S; Hoffmann R; Muskens F; Voehringer D. 2010. Alternatively activated macrophages inhibit T-cell proliferation by Stat6-dependent expression of PD-L2. Blood 116(17):3311-20. [PubMed]
Jang S; Schaller M; Berlin AA; Lukacs NW. 2010. Notch Ligand Delta-Like 4 Regulates Development and Pathogenesis of Allergic Airway Responses by Modulating IL-2 Production and Th2 Immunity. J Immunol 185(10):5835-44. [PubMed]
Oboki K; Ohno T; Kajiwara N; Arae K; Morita H; Ishii A; Nambu A; Abe T; Kiyonari H; Matsumoto K; Sudo K; Okumura K; Saito H; Nakae S. 2010. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci U S A 107(43):18581-6. [PubMed]
Ohnmacht C; Schwartz C; Panzer M; Schiedewitz I; Naumann R; Voehringer D. 2010. Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 33(3):364-74. [PubMed]
Perona-Wright G; Mohrs K; Mayer KD; Mohrs M. 2010. Differential regulation of IL-4Ralpha expression by antigen versus cytokine stimulation characterizes Th2 progression in vivo. J Immunol 184(2):615-23. [PubMed]
Perona-Wright G; Mohrs K; Mohrs M. 2010. Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node. Nat Immunol 11(6):520-6. [PubMed]
Price AE; Liang HE; Sullivan BM; Reinhardt RL; Eisley CJ; Erle DJ; Locksley RM. 2010. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A 107(25):11489-94. [PubMed]
Tang H; Cao W; Kasturi SP; Ravindran R; Nakaya HI; Kundu K; Murthy N; Kepler TB; Malissen B; Pulendran B. 2010. The T helper type 2 response to cysteine proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling. Nat Immunol 11(7):608-17. [PubMed]
Wang Y; Souabni A; Flavell RA; Wan YY. 2010. An intrinsic mechanism predisposes foxp3-expressing regulatory T cells to th2 conversion in vivo. J Immunol 185(10):5983-92. [PubMed]
2009
Clay BS; Shilling RA; Bandukwala HS; Moore TV; Cannon JL; Welcher AA; Weinstock JV; Sperling AI. 2009. Inducible costimulator expression regulates the magnitude of Th2-mediated airway inflammation by regulating the number of Th2 cells. PLoS One 4(11):e7525. [PubMed]
Dolgachev V; Petersen BC; Budelsky AL; Berlin AA; Lukacs NW. 2009. Pulmonary IL-17E (IL-25) production and IL-17RB+ myeloid cell-derived Th2 cytokine production are dependent upon stem cell factor-induced responses during chronic allergic pulmonary disease. J Immunol 183(9):5705-15. [PubMed]
Everts B; Perona-Wright G; Smits HH; Hokke CH; van der Ham AJ; Fitzsimmons CM; Doenhoff MJ; van der Bosch J; Mohrs K; Haas H; Mohrs M; Yazdanbakhsh M; Schramm G. 2009. Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses. J Exp Med 206(8):1673-80. [PubMed]
Fukuyama T; Kasper LH; Boussouar F; Jeevan T; van Deursen J; Brindle PK. 2009. Histone acetyltransferase CBP is vital to demarcate conventional and innate CD8+ T-cell development. Mol Cell Biol 29(14):3894-904. [PubMed]
King IL; Mohrs M. 2009. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med 206(5):1001-7. [PubMed]
McKee AS; Munks MW; MacLeod MK; Fleenor CJ; Van Rooijen N; Kappler JW; Marrack P. 2009. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol 183(7):4403-14. [PubMed]
Mingueneau M; Roncagalli R; Gregoire C; Kissenpfennig A; Miazek A; Archambaud C; Wang Y; Perrin P; Bertosio E; Sansoni A; Richelme S; Locksley RM; Aguado E; Malissen M; Malissen B. 2009. Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor. Immunity 31(2):197-208. [PubMed]
Moore ML; Newcomb DC; Parekh VV; Van Kaer L; Collins RD; Zhou W; Goleniewska K; Chi MH; Mitchell D; Boyce JA; Durbin JE; Sturkie C; Peebles RS Jr. 2009. STAT1 negatively regulates lung basophil IL-4 expression induced by respiratory syncytial virus infection. J Immunol 183(3):2016-26. [PubMed]
Ohnmacht C; Voehringer D. 2009. Basophil effector function and homeostasis during helminth infection. Blood 113(12):2816-25. [PubMed]
Rangel-Moreno J; Moyron-Quiroz JE; Carragher DM; Kusser K; Hartson L; Moquin A; Randall TD. 2009. Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity 30(5):731-43. [PubMed]
Reinhardt RL; Liang HE; Locksley RM. 2009. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol 10(4):385-93. [PubMed]
Sokol CL; Chu NQ; Yu S; Nish SA; Laufer TM; Medzhitov R. 2009. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol 10(7):713-20. [PubMed]
Wojciechowski W; Harris DP; Sprague F; Mousseau B; Makris M; Kusser K; Honjo T; Mohrs K; Mohrs M; Randall T; Lund FE. 2009. Cytokine-producing effector B cells regulate type 2 immunity to H. polygyrus. Immunity 30(3):421-33. [PubMed]
Yang XO; Angkasekwinai P; Zhu J; Peng J; Liu Z; Nurieva R; Liu X; Chung Y; Chang SH; Sun B; Dong C. 2009. Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat Immunol 10(12):1260-6. [PubMed]
Zaretsky AG; Taylor JJ; King IL; Marshall FA; Mohrs M; Pearce EJ. 2009. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 206(5):991-9. [PubMed]
Model validation
IL-4 is the canonical marker of Th2 cells and is known to induce differentiation of naive helper T cells to Th2 cells by polarizing the immune response toward a humoral effector response.
In contrary to other existing IL-4 reporter models generated by random insertion, this Knockin mouse line preserves the physiological expression of IL-4 and enables monitoring of Th2 activity.
No deregulation of endogenous IL-4 expression:
- Endogenous IL-4 is expressed and functional: reporter gene inserted in the 3'UTR of the endogenous IL-4 locus
- Genetic manipulation inserted is controlled
- Reporter faithfully mirrors IL-4 expression
Suitable model for your Th2 polarization monitoring studies:
- IL-4 expressing cells could be directly detected by monitoring eGFP expression (Fig. 1)
- Uncompromised immune system: intact production of IL-4 in response to infection or challenge (Fig. 2)
- Optimum monitoring of Th2 cell trafficking and cell sorting
|
Fig. 1) eGFP expression correlates with IL-4-expressing T cells and reflects IL-4 production A: In contrast to Th1 conditions, the Th2-specific conditions on a 4get cell's eGFP- population, leads to a great increase expression of eGFP, reflecting IL-4 production. Purified, naive CD4+ eGFP- homozygous 4get T cells were labeled with PKH26 red fluor. Cells were cultured under Th1, neutral, or Th2 conditions in the presence of antigen-presenting cells and analyzed on day 4, after gating on CD4+ cells. B: Only under Th2 conditions did 4get cells specifically express IL-4. Splenocytes from wild-type (+/+, open bars) and heterozygous (+/4get, hatched bars) or homozygous (4get/4get, dark bars) 4get mice were depleted of CD8+ cells by complement lysis and stimulated under Th1 or Th2 conditions for 5 days. Cells were washed and re-stimulated and supernatants were collected after 48 hours and analyzed for IL-4 and IFN-γ by ELISA. Mean and positive standard deviations of triplicate cultures are shown. |
|
Fig. 2) 4get cells retain the capacity to respond to N. brasiliensis infection in vivo by producing huge amount of IL-4.
Homozygous 4get mice were infected with N. brasiliensis. FACS analysis of lung, mesenteric lymph nodes (MLN), peripheral lymph nodes (PLN), and spleen (SPL) was performed after 10 days. Cells from the forward- and sidescatter lymphocyte gate were examined for CD4 and eGFP expression. Non-infected control mice were housed in the same facility as infected mice. Cells from three mice were pooled for each analysis. Numbers indicate percentages per quadrant. |
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