Thymic stromal lymphopoietin (TSLP) is an important factor involved in the pathogenesis of asthma and allergy. Mucosal tolerance is induced early in life and is an important mechanism of protection from allergic diseases such as asthma. Our preliminary results demonstrate that neonatal CD4+ T cells are tolerogenic and, even when immunized with OVA+Alum, preferentially differentiate into inducible regulatory T cells (iTregs) rather than T helper 2 (Th2) cells. We find that infants (age range 6-18 months) with atopic dermatitis (AD) have elevated serum TSLP (200 - 300 pg/ml), a concentration sufficient to suppress iTreg differentiation. Failed to establish airway tolerance against a particular aerosol antigen, the individuals may become sensitized at a later time in the presence of natural adjuvants such as microbial products in the environment. Recent studies show that majority household dust extracts contain bacterial-derived glycolipids capable of activating human and mice NKT cells and thus act as natural adjuvants to promote Th2 sensitization against aerosol allergens. We surprisingly find that this glycolipid-induced Th2 sensitization requires TSLP, and the mechanism underlying this requirement is unknown. Taken together, we hypothesize that skin-derived TSLP in young infants disrupts the establishment of tolerance in airway mucosa, rendering them more susceptible to be sensitized against environmental antigens in the presence of natural adjuvant-induced TSLP, the two-step mechanism underlying the atopic march. Thus, we will test our hypothesis in two Specific Aims. 1) Define the role of skin-derived TSLP in the regulation of airway tolerance. 2) Define the role of TSLP in NKT cell activation-mediated Th2 polarization in airway mucosa. The information learned from these studies will provide a greater understanding of the role of TSLP in asthma pathogenesis, and insights in targeting TSLP to prevent atopic march.
Studies from our lab and several others demonstrate that TSLP is important for the pathogenesis of asthma and allergy. In this proposal we will determine how skin-derived TSLP interrupts airway mucosal tolerance in infants when tolerance against environmental antigens should be established. We will also define the functions of TSLP in NKT cell activation-induced sensitization against the aerosol allergen.
|Du, Jianguang; Wang, Qun; Ziegler, Steven F et al. (2018) FOXP3 interacts with hnRNPF to modulate pre-mRNA alternative splicing. J Biol Chem 293:10235-10244|
|Zeng, Wei-Ping; McFarland, Margaret M; Zhou, Baohua et al. (2017) Staphylococcal enterotoxin A-activated regulatory T cells promote allergen-specific TH2 response to intratracheal allergen inoculation. J Allergy Clin Immunol 139:508-518.e4|
|Stier, Matthew T; Bloodworth, Melissa H; Toki, Shinji et al. (2016) Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. J Allergy Clin Immunol 138:814-824.e11|
|Yang, Xiaowei; Zhu, Jingjing; Tung, Chun-Yu et al. (2015) Lunasin alleviates allergic airway inflammation while increases antigen-specific Tregs. PLoS One 10:e0115330|
|Sehra, Sarita; Yao, Weiguo; Nguyen, Evelyn T et al. (2015) TH9 cells are required for tissue mast cell accumulation during allergic inflammation. J Allergy Clin Immunol 136:433-40.e1|
|Wang, Qun; Du, Jianguang; Zhu, Jingjing et al. (2015) Thymic stromal lymphopoietin signaling in CD4(+) T cells is required for TH2 memory. J Allergy Clin Immunol 135:781-91.e3|
|Yao, S; Jiang, L; Moser, E K et al. (2015) Control of pathogenic effector T-cell activities in situ by PD-L1 expression on respiratory inflammatory dendritic cells during respiratory syncytial virus infection. Mucosal Immunol 8:746-59|
|Tung, Chun-Yu; Lewis, David E; Han, Ling et al. (2014) Activation of dendritic cell function by soypeptide lunasin as a novel vaccine adjuvant. Vaccine 32:5411-9|
|Turner, Matthew J; Zhou, Baohua (2014) A new itch to scratch for TSLP. Trends Immunol 35:49-50|
|Han, Hongwei; Headley, Mark B; Xu, Whitney et al. (2013) Thymic stromal lymphopoietin amplifies the differentiation of alternatively activated macrophages. J Immunol 190:904-12|
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