Changes to the symbiotic microbiota early in life, or the absence of it, can lead to exacerbated type 2 immunity and allergic inflammations. Although it is unclear how the microbiota regulates type 2 immunity, it is a strong inducer of proinflammatory T helper 17 (T(H)17) cells and regulatory T cells (T(regs)) in the intestine. Here, we report that microbiota-induced T(regs) express the nuclear hormone receptor RORγt and differentiate along a pathway that also leads to T(H)17 cells. In the absence of RORγt(+) T(regs), T(H)2-driven defense against helminths is more efficient, whereas T(H)2-associated pathology is exacerbated. Thus, the microbiota regulates type 2 responses through the induction of type 3 RORγt(+) T(regs) and T(H)17 cells and acts as a key factor in balancing immune responses at mucosal surfaces.

Lack of immunological tolerance against self-antigens results in autoimmune disorders. During onset of autoimmunity, dendritic cells (DCs) are thought to be critical for priming of self-reactive T cells that have escaped tolerance induction. However, because DCs can also induce T cell tolerance, it remains unclear whether DCs are required under steady-state conditions to prevent autoimmunity. To address this question, we crossed CD11c-Cre mice with mice that express diphtheria toxin A (DTA) under the control of a loxP-flanked neomycin resistance (neoR) cassette from the ROSA26 locus. Cre-mediated removal of the neoR cassette leads to DTA expression and constitutive loss of conventional DCs, plasmacytoid DCs, and Langerhans cells. These DC-depleted (ΔDC) mice showed increased frequencies of CD4 single-positive thymocytes and infiltration of CD4 T cells into peripheral tissues. They developed spontaneous autoimmunity characterized by reduced body weight, splenomegaly, autoantibody formation, neutrophilia, high numbers of Th1 and Th17 cells, and inflammatory bowel disease. Pathology could be induced by reconstitution of wild-type (WT) mice with bone marrow (BM) from ΔDC mice, whereas mixed BM chimeras that received BM from ΔDC and WT mice remained healthy. This demonstrates that DCs play an essential role to protect against fatal autoimmunity under steady-state conditions.

Basophils are associated with T helper 2 (Th2) cell-polarized immune responses such as allergic disorders or helminth infections. To directly address the role of basophils for type 2 immunity, we generated transgenic mice with constitutive and selective deletion of basophils. Differentiation and accumulation of Th2 cells, induction of eosinophilia, and increase in serum IgE or IgG1 induced by allergens or by infection with the helminth Nippostrongylus brasiliensis appeared to be basophil independent. Further, basophils were not required for passive IgE- or IgG1-mediated systemic anaphylaxis. However, basophils were essential for IgE-meditated chronic allergic dermatitis and for protection against secondary infection with N. brasiliensis. These results demonstrate that basophils play an important role for protective immunity against helminths and orchestrate chronic allergic inflammation, whereas primary Th2 cell responses can operate efficiently in the absence of this cell type.

Microbiota drive tertiary lymphoid tissue formation in mice lacking the nuclear hormone receptor Rorγt, leading to intestinal inflammation and wasting disease.