CD4+ αβ T cell infiltration into the leptomeninges of lumbar dorsal roots contributes to the transition from acute to chronic mechanical allodynia after adult rat tibial nerve injuries.

Although over the past decade numerous animal studies have established that T cells play a role in neuropathic pain following peripheral nerve injury, there are contrasting reports regarding the exact location and function of these cells along the somatosensory pathway. This is presumably due to several sources of variation, including the chosen species, strain, gender and neuropathic pain model used.

In this interesting study, Bin Du et al. asked where T cells infiltrate along the somatosensory pathway in a rat model of neuropathic pain. The authors report that T cells, predominantly CD4+ helper T cells, selectively infiltrate into the leptomeninges (the arachnoid and the pia mater) of the lumbar dorsal roots after tibial nerve injury in Sprague Dawley rats. Other studies using models of autoimmune inflammation, such as experimental autoimmune encephalomyelitis, indicate that the leptomeninges represent an important checkpoint for T cell infiltration of the CNS. Interestingly, however, while T cells were found in the leptomeninges of the dorsal roots at 5 and 7 days after nerve injury, no T cells were observed in the ipsilateral L4 DRGs and dorsal horn of the spinal cord parenchyma.  

Using surgical removal of various lymph nodes prior to nerve injury, the lumbar lymph nodes were identified as the origin of T cells in the leptomeninges, but not of T cells in the injured nerve itself. Importantly, removal of these lymph nodes protected animals against the development of mechanical allodynia from day 4 after injury and was associated with reduced astrogliosis and reduced PKC-gamma expression in excitatory interneurons in the spinal cord dorsal horn. Removal of other lymph nodes, such as the popliteal lymph nodes, reduced the numbers of infiltrated T cells in the injured nerve without affecting the numbers of T cells in the leptomeninges, and did not modulate the development of mechanical allodynia.

Supporting the role of T cells within the leptomeninges in the development of chronic mechanical allodynia, intrathecal application of a neutralising antibody against the alpha beta T cell receptor caused a significant reduction in T cell numbers and attenuated mechanical pain hypersensitivity in nerve-injured rats.

In summary, this important study provides evidence that T cell infiltration into the leptomeninges of lumbar dorsal roots plays a central role in the chronic phase of mechanical pain hypersensitivity. In addition, it highlights the leptomeninges as a novel neuroimmune interface that contributes to the transition from acute to chronic pain following nerve injury. As is often the case with scientific studies, we are left with more questions than we started with. What is the specific sub-type and antigen specificity of these T cells? How do these T cells affect pain hypersensitivity, spinal astrocytes, and excitatory interneurons from the leptomeninges in the absence of evidence they infiltrate into the parenchyma? Is the T cell effect direct or indirect? Do females exhibit a similar pattern of T cell infiltration into the leptomeninges of lumbar dorsal roots? Further research into these aspects should yield clear answers in the near future.