SUMMARY Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2−/− mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as has been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons and abnormal neuronal network activity. In addition, treatment with the FDA approved drug risperidone, ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.

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Germinal center (GC) B cells undergo affinity selection, dependent upon interactions with CD4+ follicular helper T (TFH) cells. We demonstrate that TFH cells progressed through transcriptionally and functionally distinct stages, providing differential signals for GC regulation. They initially localized proximally to mutating B cells, secreted IL-21, induced expression of the transcription factor Bcl-6 and selected high affinity B cell clones. As the GC response evolved, TFH cells extinguished IL-21 and switched to IL-4 production, showed robust CD40 ligand expression and promoted the development of antibody-secreting B cells via upregulation of the transcription factor Blimp-1. Thus, TFH cells in the B cell follicle progressively differentiated through stages of localization, cytokine production and surface ligand expression to fine-tune of the GC reaction.

Graft-versus-host disease (GVHD) is a major obstacle in allogeneic hematopoietic cell transplantation. Given the dynamic changes in immune cell subsets and tissue organization, which occur in GVHD, localization and timing of critical immunological events in vivo may reveal basic pathogenic mechanisms. To this end, we transplanted luciferase-labeled allogeneic splenocytes and monitored tissue distribution by in vivo bioluminescence imaging. High-resolution analyses showed initial proliferation of donor CD4 ؉ T cells followed by CD8 ؉ T cells in secondary lymphoid organs with subsequent homing to the intestines, liver, and skin. Transplantation of purified naive T cells caused GVHD that was initiated in secondary lymphoid organs followed by target organ manifestation in gut, liver, and skin. IntroductionAllogeneic hematopoietic cell transplantation (HCT) has proven to be an effective therapy for a variety of life-threatening malignancies. 1 The beneficial effects of HCT are due to the graft-versustumor reaction, which is capable of destroying residual tumor cells that persist after chemotherapy or radiation therapy. 2 However, allogeneic HCT is limited by the immunologic recognition and destruction of host tissues, termed graft-versus-host disease (GVHD). Acute GVHD continues to be a major source of morbidity and mortality following HCT, which limits treatment of a broader spectrum of diseases, such as autoimmune diseases or organ transplant rejection. 3,4 Tissue-specific destruction of GVHD target organs, as gastrointestinal tract, liver, and skin, underlines the importance of migration capacities of alloreactive T lymphocytes. 5,6 In the current study we aimed to determine the time points of organ infiltration and focused on the role of different lymphoid organs in initiating acute GVHD. We used in vivo bioluminescence imaging (BLI) to analyze the migration pattern of whole splenocytes after transplantation into allogeneic recipients. BLI has already proven to be a sensitive and accurate means of characterizing engraftment patterns of hematopoietic stem cells, of monitoring tumor cell growth, and of assessing response to conventional and biological therapies. [7][8][9] We also aimed to clarify the role of different T-cell subsets during GVHD development. It is reported in the literature [10][11][12] that CD4 ϩ effector memory T (T EM ) cells do not cause GVHD. This prompted us to characterize their trafficking and proliferation pattern in vivo, while comparing it to purified naive CD4 ϩ T lymphocytes. Materials and methods MiceFVB/N (H-2 q , Thy1.1) mice and Balb/c mice (H-2 d , Thy1.2) were purchased from Jackson Laboratory (Bar Harbor, ME). The luciferaseexpressing (luc ϩ ) transgenic FVB/N line was generated as previously described. 9 Female heterozygous luc ϩ offspring of the transgenic founder line FVB-L2G85 were used for all transplantation experiments. All animal studies were performed under institutional approval. Flow cytometric cell purification and analysisThe following antibodies were purchased from...