There is increasing evidence that CD4(+) T-cell-dependent responses are 
associated with the maintenance of neuropathic pain. However, little is known 
about the precise mechanism(s) underlying the activation of CD4(+) T-cells. We 
herein show that inhibition of cathepsin S (CatS) activity, either through 
genetic deletion or via a pharmacological inhibitor, Z-Phe-Leu-COCHO (Z-FL), 
significantly attenuated the maintenance of tactile allodynia, splenic 
hypertrophy, increased number of splenic CD4(+) T-cells and the final cleavage 
step of the MHC class II-associated invariant chain following peripheral nerve 
injury. It was also noted that splenectomy significantly attenuated the 
peripheral nerve injury-induced tactile allodynia, whereas the adoptive transfer 
of splenic CD4(+) T-cells from neuropathic wild-type mice significantly 
increased the pain level of splenectomized wild-type or CatS(-/-) mice. 
Furthermore, CatS deficiency or Z-FL treatment also significantly inhibited the 
infiltration of CD4(+) T-cells that expressed interferon-γ (IFN-γ) in the dorsal 
spinal cord. Signal transducer and activator of transcription 1, a molecule 
downstream of IFN-γ receptor activation, was activated exclusively in microglia 
7 d after peripheral nerve injury. Moreover, CatS deficiency, Z-FL treatment, or 
splenectomy significantly attenuated the proliferation of microglia 14 d after 
peripheral nerve injury. These results show a peripheral pivotal role of CatS in 
the development of neuropathic pain through the antigen-specific activation of 
CD4(+) T-cells. After activation, CD4(+) T-cells infiltrate into the dorsal 
spinal cord and secrete IFN-γ to reactivate microglia, which contribute to the 
transition of acute pain to a chronic pain state.