Intestinal challenges shape the polarisation of dural meninges memory CD4+ T cells

Abstract

The central nervous system (CNS) and the barriers that protect it, including the three-layered meninges, have been thought to be mostly devoid of immune cells and to interact sparingly with the peripheral immune system. However, recent work has shown that a diverse array of both innate and adaptive immune cells populate distinct niches of the brain and its borders and respond to insults from both within, and outside of, the CNS. The dura mater is the thickest and outermost skull-adjacent layer of the meninges, the membranes surrounding the brain and spinal cord, and has been shown to be particularly enriched in immune cell networks. Our lab has previously shown that the humoral immune landscape of the dura is intimately associated with that of the intestinal tract, in part reflecting the need of the dura to defend the underlying brain from intestinally derived blood-borne threats. Adaptive CD4+ T cells have been shown to populate the dura mater, but their phenotypic or clonal relationship to gut counterparts or role in local anti-pathogenic immune responses has been less studied. Using mouse models, we show that dural CD4+ T cell effector states are highly responsive to intestinal perturbations. We show that dural CD4+ T cell polarisation to a T-helper (Th)1, Th2, or Th17 state is predicated on the prevailing intestinal challenge, including bacterial and parasitic infections, as well as chemical-induced colitis. Using pathogens expressing specific model antigens, we show that the dural CD4+ T cell population contains cells bearing T-cell receptors (TCRs) specific for gut pathogens. This accumulation of dural antigen-specific CD4+ T cells depended, at least in part, on a CXCR6-CXCL16 axis. These dural antigen specific CD4+ T cells are long-lived and remain capable of a recall response following intravenous re- challenge for months after the initial oral infection. Using single-cell RNA sequencing, we identified clonal expansion of a population of dural CD4+ T cells expressing markers of tissue- residency. Finally, we show that dural CD4+ T cells induced by intestinal infection may help defend the brain against invasion by intravenous pathogens. Our work further delineates the intimate relationship between gut and dural immunity and reveals that CD4+ T cells form an integral component of the gut-dura axis. Further interrogation of the links between gut and dural CD4+ T cells may lead to a better understanding of how this axis may be therapeutically manipulated to promote host protection against infectious diseases of the CNS.