Abstract
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.
Highlights
A role for cellular immunity in neurodevelopmental disorders is suggested by prominent adaptive and innate immune abnormalities in autism, attention deficit, schizophrenia, and related conditions [1, 2]
Addition of anti-CD103 antibody, while inconsequential by itself, induced much more marked β-catenin cleavage when combined with CD8 T cells in co-culture (Figure 1C), notably resulting in a prominent low molecular weight β-catenin species associated with cell proliferation in inflamed and cancerous cells [24]
It is formally possible that blocking CD103 ligation with the M290 antibody is responsible for the observed effects on Neural Progenitor Cells (NPCs) proliferation, we consider its co-stimulatory activity on CD103+ T cells a more likely explanation when considered together with cell cycle data
Summary
A role for cellular immunity in neurodevelopmental disorders is suggested by prominent adaptive and innate immune abnormalities in autism, attention deficit, schizophrenia, and related conditions [1, 2]. The specific contribution of adaptive cellular immunity to discrete neurodevelopmental conditions remains poorly defined, and discrete changes in cellular immune effectors have not been linked to particular neurodevelopmental disorder(s) Both autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) are associated with increases in adaptive immune (T) cell cytokines, Th2-like cytokines (IL4, IL-6, and/or IL-10), or decreases in Th2-like cytokines (IL-2 and/or IFNγ ) [3, 4]. Among the most prominent elements of the adaptive immune subcompartment are tissue-resident memory CD8 T cells derived from recent thymic emigrants that express the αE integrin (CD103) [8] In this context, CD103 is known to function as an E-cadherin receptor, facilitating T cell binding to epithelial cell surfaces and tissue entry across epithelial cell barriers such as gut and brain [8,9,10]. T cell production and emigration to the general circulation coincides with critical milestones in higher brain development, including gliogenesis, synaptogenesis, and apoptosis [12, 13]
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