Mechanism of basophil mediated immune modulation

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DESCRIPTION (provided by applicant): Basophils are now recognized as critical effectors and immune modulators during Th2 mediated immune responses, such as allergic inflammations and parasite infections. Evidence suggests that basophils produce Th2 inducing factors including IL-4, the signature cytokine of Th2 immunity, thus inducing Th2 differentiation of activated naive CD4 T cells. However, given that basophils are mostly found in the circulation during steady- state conditions, how basophils contribute to the Th2 differentiation remain unknown. A recent study reported that basophils are transiently recruited into the draining lymph nodes upon allergen immunization, promoting Th2 differentiation. Consistent with this, we found transient basophil recruitment into the draining lymph node following parasite injection. Interestingly, IL-3 plays a crucial role in basophil recruitment as the recruitment was absent in IL-3 KO mice injected with parasites. Lymph node entry of adoptively transferred basophils was abolished after treatment with pertussis toxin, suggesting the involvement of chemokine/chemokine receptor interaction. Coinjection of OVA protein with parasites preferentially induces OVA-specific IL-4 producing T cell immunity within the draining lymph nodes, strongly suggesting that recruited basophils may be involved in mediating the Th2 immunity. Based on these results, we propose the hypothesis that IL-3 produced by activated T cells within the lymph nodes stimulates IL-3R+ target cells to recruit circulating basophils, thus promoting Th2 differentiation. Two specific aims will be tested to address the hypothesis. Aim #1 will test the contribution of IL-3 to the developing Th2 immunity via basophil recruitment. Aim #2 will define targets of IL-3 involved in basophil lymph node recruitment. Elucidating how basophils are recruited into tissues such as lymphoid or inflamed tissues will provide critical insights into understanding in vivo contribution of basophils to developing Th2 immunity as well as to basophil mediated pathology found in allergic inflammation including asthma. PUBLIC HEALTH RELEVANCE: Evidence indicating that basophils play critical roles in type 2 mediated immune responses found in allergic inflammations as well as parasitic infections is increasing. This proposal aims to investigate poorly defined mechanism by which basophils modulate immune responses. The results may allow us to better understand in vivo roles of these rare yet potent cells and to develop novel strategies to prevent basophil mediated pathology often found in allergic inflammations such as asthma.