Direct actions of TSLP on CD4+ T cells are important for in vivo Th2-type responses (P6252)

Abstract

Abstract TSLP is a pleiotropic cytokine that has broad effects in multiple T helper type 2 (Th2) driven immune responses, including in asthma, intestinal immunity, and tumor progression. Initially, TSLP was shown to indirectly influence CD4+ T cells through direct actions on dendritic cells, resulting in CD4+ T cell priming towards a Th2 polarized response. Subsequently, direct actions of TSLP on CD4+ T cells were also demonstrated, but these direct actions were not analyzed in vivo. Herein, we show that TSLP induces both Th2 (IL-4, 5, 13) and Th2-associated (IL-3, 9, 10 and 31) cytokines early after TCR activation. Interestingly, TSLP can increase IL-5 production independent of IL-2 and IL-4 signaling; however, production of the other Th2 cytokines was a least partially dependent on IL-2 and IL-4. Additionally, we demonstrated that direct actions of TSLP on CD4+ T cells were important for Th2 polarization and cytokine production in an in vivo mouse lung inflammation model. Lastly, we found that TSLP plays a role in the development of IL-9 producing cells during a mouse chronic asthma model. Taken together, these data indicate a role for critical direct actions of TSLP in Th2 responses in vivo and indicate strategies for manipulating Th2 responses, including in allergic disease.