TREGking From Gut to Brain: The Control of Regulatory T Cells Along the Gut-Brain Axis.

The human gastrointestinal tract has an enormous and diverse microbial community, termed microbiota, that is necessary for the development of the immune system and tissue homeostasis. In contrast, microbial dysbiosis is associated with various inflammatory and autoimmune diseases as well as neurological disorders in humans by affecting not only the immune system in the gastrointestinal tract but also other distal organs. FOXP3+ regulatory T cells (Tregs) are a subset of CD4+ helper T cell lineages that function as a gatekeeper for immune activation and are essential for peripheral autoimmunity prevention. Tregs are crucial to the maintenance of immunological homeostasis and tolerance at barrier regions. Tregs reside in both lymphoid and non-lymphoid tissues, and tissue-resident Tregs have unique tissue-specific phenotype and distinct function. The gut microbiota has an impact on Tregs development, accumulation, and function in periphery. Tregs, in turn, modulate antigen-specific responses aimed towards gut microbes, which supports the host-microbiota symbiotic interaction in the gut. Recent studies have indicated that Tregs interact with a variety of resident cells in central nervous system (CNS) to limit the progression of neurological illnesses such as ischemic stroke, Alzheimer's disease, and Parkinson's disease. The gastrointestinal tract and CNS are functionally connected, and current findings provide insights that Tregs function along the gut-brain axis by interacting with immune, epithelial, and neuronal cells. The purpose of this study is to explain our current knowledge of the biological role of tissue-resident Tregs, as well as the interaction along the gut-brain axis.

Involvement of Denervated Midbrain-Derived Factors in the Formation of Ectopic Cortico-Mesencephalic Projection after Hemispherectomy.

Neuronal remodeling after brain injury is essential for functional recovery. After unilateral cortical lesion, axons from the intact cortex ectopically project to the denervated midbrain, but the molecular mechanisms remain largely unknown. To address this issue, we examined gene expression profiles in denervated and intact mouse midbrains after hemispherectomy at early developmental stages using mice of either sex, when ectopic contralateral projection occurs robustly. The analysis showed that various axon growth-related genes were upregulated in the denervated midbrain, and most of these genes are reportedly expressed by glial cells. To identify the underlying molecules, the receptors for candidate upregulated molecules were knocked out in layer 5 projection neurons in the intact cortex, using the CRISPR/Cas9-mediated method, and axonal projection from the knocked-out cortical neurons was examined after hemispherectomy. We found that the ectopic projection was significantly reduced when integrin subunit ß three or neurotrophic receptor tyrosine kinase 2 (also known as TrkB) was knocked out. Overall, the present study suggests that denervated midbrain-derived glial factors contribute to lesion-induced remodeling of the cortico-mesencephalic projection via these receptors.SIGNIFICANCE STATEMENT After brain injury, compensatory neural circuits are established that contribute to functional recovery. However, little is known about the intrinsic mechanism that underlies the injury-induced remodeling. We found that after unilateral cortical ablation expression of axon-growth promoting factors is elevated in the denervated midbrain and is involved in the formation of ectopic axonal projection from the intact cortex. Evidence further demonstrated that these factors are expressed by astrocytes and microglia, which are activated in the denervated midbrain. Thus, our present study provides a new insight into the mechanism of lesion-induced axonal remodeling and further therapeutic strategies after brain injury.