Gateway reflexes: A new paradigm of neuroimmune interactions

The immune system is affected considerably by the physical environment. The molecular mechanisms that regulate this connection are not well understood. Because neural activities sense the environment, it has been hypothesized that neural signals transduce environmental stimulations into immune responses. Recently, we discovered that regional neural activations change the dynamics of immune cell migration through the activity of endothelial cells by using a multiple sclerosis model, experimental autoimmune encephalomyelitis. More specifically, we identified the dorsal vessels of the fifth lumbar (L5) spinal cord as the initial entry site of pathogenic T cells. This entry site was defined by the activation of sensory neurons innervating from the soleus muscles, which are the main antigravity muscles. The resulting sensory neural activation created a gateway through the activation of regional sympathetic pathways to increase the expression of chemokines at the dorsal vessels of the L5 spinal cord, attracting autoreactive pathogenic T cells. In other experiments, we activated different regional neurons by electric pulses or pain sensation and discovered that gateways for immune cells, including autoreactive pathogenic T cells, are dependent on the site of the regional neural activation, particularly the sensory–sympathetic crosstalk. We termed these neuroimmune interactions as “gateway reflexes.” In the present review, we discuss details of the gateway reflex.