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The incidence of autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), which frequently co-occur, are both rising. The causes of ASD and ADHD remain elusive, even as both appear to involve perturbation of the gut-brain-immune axis. CD103 is an integrin and E-cadherin receptor most prominently expressed on CD8 T cells that reside in gut, brain, and other tissues. CD103 deficiency is well-known to impair gut immunity and resident T cell function, but it's impact on neurodevelopmental disorders has not been examined. We show here that CD8 T cells influence neural progenitor cell function, and that CD103 modulates this impact both directly and potentially by controlling CD8 levels in brain. CD103 knockout (CD103KO) mice exhibited a variety of behavioral abnormalities, including superior cognitive performance coupled with repetitive behavior, aversion to novelty and social impairment in females, with hyperactivity with delayed learning in males. Brain protein markers in female and male CD103KOs coincided with known aspects of ASD and ADHD in humans, respectively. Surprisingly, CD103 deficiency also decreased age-related cognitive decline in both sexes, albeit by distinct means. Together, our findings reveal a novel role for CD103 in brain developmental function, and identify it as a unique factor linking ASD and ADHD etiology. Our data also introduce a new animal model of combined ASD and ADHD with associated cognitive benefits, and reveal potential therapeutic targets for these disorders and age-related cognitive decline.

Mitigating effects of aging on human health remains elusive because aging impacts multiple systems simultaneously, and because experimental animals exhibit critical aging differences relative to humans. Separation of aging into discrete processes may identify targetable drivers of pathology, particularly when applied to human-specific features. Gradual homeostatic expansion of CD8 T cells dominantly alters their function in aging humans but not in mice. Injecting T cells into athymic mice induces rapid homeostatic expansion, but its relevance to aging remains uncertain. We hypothesized that homeostatic expansion of T cells injected into T-deficient hosts models physiologically relevant CD8 T cell aging in young mice, and aimed to analyze age-related T cell phenotype and tissue pathology in such animals. Indeed, we found that such injection conferred uniform age-related phenotype, genotype, and function to mouse CD8 T cells, heightened age-associated tissue pathology in young athymic hosts, and humanized amyloidosis after brain injury in secondary wild-type recipients. This validates a model conferring a human-specific aging feature to mice that identifies targetable drivers of tissue pathology. Similar examination of independent aging features should promote systematic understanding of aging and identify additional targets to mitigate its effects on human health.

Activation of the phosphatidylinositol-3-OH kinase (PI3K) signaling cascade is becoming increasingly recognized as a common feature of thyroid follicular neoplasms. We have recently shown that conditional loss of Pten in the mouse thyroid follicular cells is sufficient to stimulate continuous autonomous growth, leading to a homogeneously hyperplastic gland and to the development of follicular adenomas. Because the PI3K/AKT cascade can activate a plethora of different signaling pathways, it is still unclear which of these may represent the key mitogenic output of PI3K-initiated signaling. Here, we show that the in vivo proliferative response to chronic PI3K activation profoundly relies on the activation of the mammalian target of rapamycin (mTOR)/S6K1 axis, and that mTOR inhibition in Pten mutant mice and cells restores virtually normal proliferation rates, despite the presence of still elevated Akt activity, at least in part by down-regulating cyclins D1 and D3, and without affecting cell survival. [Cancer Res 2008;68(2):444–9]

Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tumors, including thyroid neoplasia. Cowden Disease patients, who harbor germ-line PTEN mutations, often display thyroid abnormalities, including multinodular goiter and follicular adenomas, and are at increased risk of thyroid cancer. To gain insights into the role PTEN plays in thyroid function and disease, we have generated a mouse strain, in which Cre-mediated recombination is used to specifically delete Pten in the thyrocytes. We found that Pten mutant mice develop diffuse goiter characterized by extremely enlarged follicles, in the presence of normal thyroid-stimulating hormone and T4 hormone levels. Loss of Pten resulted in a significant increase in the thyrocyte proliferative index, which was more prominent in the female mice, and in increased cell density in the female thyroid glands. Surprisingly, goitrogen treatment did not cause a substantial increase of the mutant thyroid size and increased only to some extent the proliferation index of the female thyrocytes, suggesting that a relevant part of the thyroid-stimulating hormone–induced proliferation signals are funneled through the phosphatidylinositol-3-kinase (PI3K)/Akt cascade. Although complete loss of Pten was not sufficient to cause invasive tumors, over two thirds of the mutant females developed follicular adenomas by 10 months of age, showing that loss of Pten renders the thyroid highly susceptible to neoplastic transformation through mechanisms that include increased thyrocyte proliferation. Our findings show that constitutive activation of the PI3K/Akt cascade is sufficient to stimulate continuous autonomous growth and provide novel clues to the pathogenesis of Cowden Disease and sporadic nontoxic goiter. [Cancer Res 2007;67(3):959–66]

G A A b st ra ct s in colonoid culture and we posit that activation of the TRIF signaling pathway is the main mediator of these changes. Understanding how innate immune recognition pathways crosstalk with epithelial stem cell self-renewal and differentiation pathways will be important for future studies examining the role of stem cells in homeostasis and tumor promotion. We would like to acknowledge the technical help and provision of reagents by Richard J. von Furstenberg and Susan J. Henning.

Dendritic cell (DC) vaccines for glioblastoma (GBM) can effectively extend overall patient survival, but they are not curative. Younger patients responded poorly to vaccination in ours and other trials. Mutations in isocitrate dehydrogenase 1 (IDH1) are commonly found in younger patients, encouraging the hypothesis that IDH1 mutation may subvert the clinical benefits of DC vaccination. Sequencing IDH1-mutated human GBM samples revealed an increase in IDH1 mutated tumor tissue after vaccination, consistent with this hypothesis. This led us to consider whether CTL recognition might be functionally altered by IDH1 and/or its mutation. Indeed, alloreactive CD8+ hybridoma cells exhibited significantly delayed lysis of GL26 cells expressing mutant IDH1 relative to untransfected GL26, but significantly increased lysis of GL26 transfected with unmutated IDH1. In contrast, wild-type and mutant IDH1 transfectants of GL26 exhibited identical sensitivity to imidazole-induced cell death, as well as identical MHC I expression. Moreover, preliminary studies suggest that wild-type and mutant IDH1 transfectants of GL26 are differentially sensitive to DC vaccination, with mutant IDH1 abrogating the longer survival conferred by such treatment. We therefore examined the possibility that these observed differences were mediated by a novel, immune-specific property of IDH1. Generalized sialidase activity can de-sialylate the CD8 coreceptor on T cells, and such modification enhances CD8 binding to MHC I, thereby modulating T cell responsiveness to MHC I-bound peptides. As the IDH1 catalytic site is structurally similar to microbial sialidase, we hypothesized that IDH1 possesses CD8-directed sialidase activity capable of enhancing CTL lysis, and that IDH1mutation critically diminishes this activity. Accordingly, IDH1 treatment increased binding to tumor pHLA multimers and to PNA lectin by human CD8 T cells, with the pHLA binding inhibited by either free sialic acid prior to treatment, or by anti-CD3 antibody after treatment. In addition, IDH1 treatment increased binding to several tumor pMHCI multimers by mouse CD8 T cells, and markedly increased IFN-γ production in response to stimulation by such multimers. Finally, labeled IDH1 bound to the surface of spleen cells, and physiologic concentrations of IDH1 specifically associated with a putative surface heterodimer resembling the CD8 coreceptor in murine T cell lysates. Together, these results suggest that wild-type IDH1possesses immune-specific sialidase function that enhances CTL lysis. In contrast, mutant IDH1 appears to delay immune lysis of tumor cells expressing it, and abrogates vaccine benefits, potentially by diminishing its immune-specific sialidase function. Citation Format: Ryan Cordner, Michelle Jhun, Akanksha Panwar, HongQiang Wang, Nicole Yeager, Joseph McAbee, Armen Mardiros, Akane Takei, Xuemo Fan, Emmaunel Jouanneau, Keith Black, Christopher Wheeler. IDH1 modulates the immune response to glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-333. doi:10.1158/1538-7445.AM2013-LB-333

expected, several fold increase in the expressions of proinflammatory cytokines including IL-1α, IL-1β, TNF-α, IFN-γ in the DSS-treated WT mice but not in the DSS-treated Cl2TGmice suggesting potential immune tolerance/adaptation. Further assessment of proliferation and apoptosis in isolated colonic epithelial cells using BrdU and cleaved caspase-3 staining and FACS analysis showed decreased apoptosis (p

TL1A is a member of the TNF superfamily and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, a subset of Crohn's disease (CD) patients with the risk TL1A haplotype is associated with elevated TL1A expression and a more severe disease course. To investigate the in vivo role of elevated TL1A expression, we generated two transgenic (Tg) murine models with constitutive Tl1a expression in either lymphoid or myeloid cells. Compared to wildtype (WT) mice, constitutive expression of Tl1a in either lymphoid or myeloid cells showed mild patchy inflammation in the small intestine, which was more prominent in the ileum. In addition, mice with constitutive Tl1a expression exhibited enhanced intestinal and colonic fibrosis compared to WT littermates. The percentage of T cells expressing the gut homing chemokine receptors CCR9 and CCR10 was higher in the Tl1a Tg mice compared to WT littermates. Sustained expression of Tl1A in T cells also lead to increased Foxp3+ Treg cells. T cells or antigen presenting cells (APC) with constitutive expression of Tl1a were found to have a more activated phenotype and mucosal mononuclear cells exhibit enhanced Th1 cytokine activity. These results indicated an important role of TL1A in mucosal T cells and APC function and showed that up-regulation of TL1A expression can promote mucosal inflammation and gut fibrosis.