Loss of T cells influences sex differences in stress-related gene expression

Abstract

Deficiencies in the adaptive immune system have been linked to anxiety-like behaviours and stress reactivity. Mice lacking T lymphocytes through knockout of the T cell receptor (TCR) β and δ chains were compared to wild type C57Bl/6 mice. Central stress circuitry gene expression was assessed following repeated restraint stress. TCRβ−/−δ−/− mice showed an increased baseline plasma corticosterone and exaggerated changes in stressrelated gene expression after repeated restraint stress. Sexual dimorphic stress responses were observed in wildtype C57Bl/6 mice but not in TCRβ−/−δ−/− mice. These data suggest that T cell-brain interactions influence sex-differences in CNS stress circuitry and stress reactivity.

Microbe-Immune Crosstalk: Evidence That T Cells Influence the Development of the Brain Metabolome

“…In addition to a detailed map of the impact of T-cell deficiency on the microbial-metabolomic profile in the gut, this study demonstrated T-cell deficiency on development of the brain metabolome, with higher abundance of GABA, glycine, aspartate, acetate and glycerophosphocholine in the brains of TCR β–/–δ–/– mice across the lifespan. A role for T-cells in modulating brain development has been established, with previous studies showing changes in the volume of several brain regions in TCR β–/–δ–/– mice [ 13 ], paralleled by decreased anxiety-like behaviour, but elevated basal cortisol in TCR β–/–δ–/– mice [ 13 , 14 ]. Further, IL-17a released by meningeal γδ T-cells have also been shown to modulate anxiety-like behavior [ 2 ], and effect that may be mediated by microglia by inducing phagocytosis of neural progenitor cells [ 42 ].…”

“…While not directly tested here, this is consistent with the changes in GABA in the present study in the frontal cortex, hippocampus and hypothalamus. Additional work is needed to demonstrate whether such alterations are the molecular basis for the abnormalities in anxiety-like behavior in TCR β–/–δ–/– mice [ 13 , 14 ]. In addition, the reported negative association between anxiety and fecal abundance of Muribaculaceae in humans [ 50 ] is intriguing and we suggest that this behavioral trait may be responsive to the changes in the microbiota of TCR β–/–δ–/– mice.…”

“…Previous work from our group based on studies of different models of combined immunodeficiencies [ 11 , 12 ] showed that mice depleted of T-cells via knock-out of the β and δ chains of the T-cell receptor ( TCR β–/–δ–/–) exhibited decreased anxiety-like behaviour, but elevated baseline plasma corticosterone and enhanced gene expression changes in response to stress than C57Bl/6 (B6) mice [ 13 , 14 ], similar to what was previously reported in GF mice [ 15 , 16 , 17 ]. These behavioral and physiological alterations were paralleled by changes in the volume of several brain regions [ 13 ].…”

“…In this study, a longitudinal design was used to map the temporal gut microbial and gut/brain metabolomic trajectory during postnatal development spanning from early-life to adulthood in wild type B6 and T cell deficient mice ( TCR β–/–δ–/– ) [ 13 , 14 , 18 ]. Our data showed that compared to B6 mice, TCR β–/–δ–/– mice had an altered trajectory of microbiome maturation, reduced alpha diversity, several differences in microbial composition, including increased abundance of Akkermansia and reduced abundance of Rosburia, and changes in gut and brain metabolite profiles.…”

Microbe–Immune–Stress Interactions Impact Behaviour during Postnatal Development

“…In parallel with these observations, T-cell-deficient ( TCRβ-/-δ-/-) mice display abnormalities in both anxiety-like behaviour [ 16 ] and hypothalamic pituitary axis (HPA)-mediated stress response [ 17 ]. These behavioural changes were accompanied by a genotype-specific microbiome and metabolite signature, which was coincident with altered levels of neuroactive metabolites in the brain [ 18 ].…”