Activator protein 1 (AP-1) transcription factors are dimers of Jun, Fos, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains1. Many AP-1 proteins contain defined transcriptional activation domains (TADs), but Batf and the closely related Batf3 (refs 2, 3) contain only a basic region and leucine zipper and have been considered inhibitors of AP-1 activity3–8. Here we show that Batf is required for the differentiation of IL-17-producing T helper (TH17) cells9. TH17 cells comprise a CD4+ T cell subset that coordinates inflammatory responses in host defense but is pathogenic in autoimmunity10–13.Batf −/−mice have normal TH1 and TH2 differentiation, but show a defect in TH17 differentiation, and are resistant to experimental autoimmune encephalomyelitis (EAE).Batf −/−T cells fail to induce known factors required for TH17 differentiation, such as RORγt11 and the cytokine IL-21 (refs 14–17). Neither addition of IL-21 nor overexpression of RORγt fully restores IL-17 production in Batf−/− T cells. The IL-17 promoter is Batf-responsive, and upon TH17 differentiation, Batf binds conserved intergenic elements in the IL-17A/F locus and to the IL-17, IL-21 and IL-22 (ref 18) promoters. These results demonstrate that the AP-1 protein Batf plays a critical role in TH17 differentiation.

The AP-1 transcription factor Batf3 is required for homeostatic development of CD8α+ classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here, we identify an alternative, Batf3-independent pathway for their development operating during infection with intracellular pathogens mediated by the cytokines IL-12 and IFN-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP-1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiologic compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA-4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP-1 factors such as Irf4 and Irf8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.

We have examined the function of TIM-1, encoded by a gene identified as an 'atopy susceptibility gene' (Havcr1*), and demonstrate here that TIM-1 is a molecule that costimulates T cell activation. TIM-1 was expressed on CD4(+) T cells after activation and its expression was sustained preferentially in T helper type 2 (T(H)2) but not T(H)1 cells. In vitro stimulation of CD4(+) T cells with a TIM-1-specific monoclonal antibody and T cell receptor ligation enhanced T cell proliferation; in T(H)2 cells, such costimulation greatly enhanced synthesis of interleukin 4 but not interferon-gamma. In vivo, the use of antibody to TIM-1 plus antigen substantially increased production of both interleukin 4 and interferon-gamma in unpolarized T cells, prevented the development of respiratory tolerance, and increased pulmonary inflammation. Our studies suggest that immunotherapies that regulate TIM-1 function may downmodulate allergic inflammatory diseases.

Respiratory exposure to antigen induces T cell tolerance via several overlapping mechanisms that limit the immune response. While the mechanisms involved in the development of Treg cells have received much attention, those that result in T cell deletion are largely unknown. Herein, we show that F4/80+ lymph node medullary macrophages expressing TIM-4, a phosphatidylserine receptor, remove antigen-specific T cells during respiratory tolerance, thereby reducing secondary T cell responses. Blockade of TIM-4 inhibited the phagocytosis of antigen-specific T cells by TIM-4 expressing lymph node medullary macrophages, resulting in an increase in the number of antigen-specific T cells and the abrogation of respiratory tolerance. Moreover, specific depletion of medullary macrophages inhibited the induction of respiratory tolerance, highlighting the key role of TIM-4 and medullary macrophages in tolerance. Therefore, TIM-4-mediated clearance of antigen specific T cells represents an important previously unrecognized mechanism regulating respiratory tolerance.

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