Transfer of in vivo primed transgenic T cells supports allergic lung inflammation and FIZZ1 and Ym1 production in an IL-4Rα and STAT6 dependent manner.
BACKGROUND
CD4+ T helper type 2 (TH2) cells, their cytokines IL-4, IL-5 and IL-13 and the transcription factor STAT6 are known to regulate various features of asthma including lung inflammation, mucus production and airway hyperreactivity and also drive alternative activation of macrophages (AAM). However, the precise roles played by the IL-4/IL-13 receptors and STAT6 in inducing AAM protein expression and modulating specific features of airway inflammation are still unclear. Since TH2 differentiation and activation plays a pivotal role in this disease, we explored the possibility of developing an asthma model in mice using T cells that were differentiated in vivo.


RESULTS
In this study, we monitored the activation and proliferation status of adoptively transferred allergen-specific naïve or in vivo primed CD4+ T cells. We found that both the naïve and in vivo primed T cells expressed similar levels of CD44 and IL-4. However, in vivo primed T cells underwent reduced proliferation in a lymphopenic environment when compared to naïve T cells. We then used these in vivo generated effector T cells in an asthma model. Although there was reduced inflammation in mice lacking IL-4Rα or STAT6, significant amounts of eosinophils were still present in the BAL and lung tissue. Moreover, specific AAM proteins YM1 and FIZZ1 were expressed by epithelial cells, while macrophages expressed only YM1 in RAG2-/- mice. We further show that FIZZ1 and YM1 protein expression in the lung was completely dependent on signaling through the IL-4Rα and STAT6. Consistent with the enhanced inflammation and AAM protein expression, there was a significant increase in collagen deposition and smooth muscle thickening in RAG2-/- mice compared to mice deficient in IL-4Rα or STAT6.


CONCLUSIONS
These results establish that transfer of in vivo primed CD4+ T cells can induce allergic lung inflammation. Furthermore, while IL-4/IL-13 signaling through IL-4Rα and STAT6 is essential for AAM protein expression, lung inflammation and eosinophilia are only partially dependent on this pathway. Further studies are required to identify other proteins and signaling pathways involved in airway inflammation.
Center for Vascular and Inflammatory Diseases, and Department of Microbiology and Immunology, University of Maryland School of Medicine, 800 W, Baltimore St, Baltimore, MD 21201, USA.
Preeta
P
Dasgupta
Svetlana P
SP
Chapoval
Elizabeth P
EP
Smith
Achsah D
AD
Keegan
D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000276:immunology*; D002478:Cells, Cultured; D003170:Complement Pathway, Alternative / Q000235:genetics; D004195:Disease Models, Animal; D018960:Hyaluronan Receptors / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D037102:Lectins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011014:Pneumonia / Q000235:genetics / Q000276:immunology*; D011657:Pulmonary Eosinophilia / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit
D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; D001619:beta-N-Acetylhexosaminidases; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C413576:Retnla protein, mouse; C429541:Chil3 protein, mouse