They also conclude that IL-13-producing Th1 and Th17 cells are relatively common, generated in response to both self and foreign antigens; during systemic autoimmune disease in lymphopenic mice, where they appear in the absence of conventional Th2 cells, and during immunization or pathological inflammation in “normal” mice, where they appear alongside conventional, RGFP966 IL-4/IL-13 double-positive Th2 cells. Based on these findings, we propose

that IL-13 production is more widespread than currently appreciated, representing a general feature of acute T-cell responses, whether Th1, Th2, or Th17, in character. This conclusion is supported by numerous studies showing that effector T-cell subsets are plastic, often exhibiting mixed cytokine profiles [5, 6], and by recent work showing (i) that Th2 cells can be converted into Th1 cells [5, 6], (ii) that Th2-type memory T cells can produce IL-17 [7, 8], (iii) that STAT3, a key pro-Th17 TF, can promote Th2-type responses [4], and (iv) that the TF NFIL3 can induce IL-13 production in Th1 cells [16]. Using a mouse model of lymphopenia-induced autoimmunity, we demonstrate that Th2-type cytokines can have profound consequences in Th1- and Th17-dominated settings. We term these Th2 responses “atypical” because they occur in a nonpermissive environment, one which favors Th1 and Th17-type responses, and because they develop in the absence of T cell-derived

IL-4, which is the hallmark of conventional Th2-type responses. Atypical Th2 responses appear to have multiple functions in sOva Rag2−/− mice; they are pathogenic and proinflammatory when acting on FK506 cell line innate and nonimmune cells, but protective and anti-inflammatory when acting on the T-cell compartment. Given that IL-13 was produced in large quantities, and known to act on a range of innate and nonimmune cells, we propose that IL-13 is responsible

for the lethal, STAT6-independent effects in this model. Further studies are needed to conclusively implicate IL-13 but this hypothesis is consistent with its known proinflammatory properties and with our finding that IL-4Rα deficiency improves the survival of sOva Rag2−/− hosts. Together with previous work, our data position IL-13 as a vital component of adaptive immune responses and suggest that manipulating this cytokine next may have therapeutic benefits in settings where “classical” Th2 cells are not evident, such as during Th1- and Th17-type inflammation. Our data indicate that IL-13 is frequently produced by Th1 and Th17 cells, and that blocking this cytokine may have therapeutic benefits in settings where classical Th2-type responses cells are not evident. DO11.10 Rag2−/− and sOva Rag2−/− mice were generated as described [14, 15]. These were crossed with congenic IL-4Rα−/− (Taconic Farms) and STAT6−/− mice (Jackson Laboratories) to generate gene-deficient D011.10+ Rag2−/− donors and gene-deficient sOva+ Rag2−/− hosts.