Background and purpose: Our previous work proved that HMGB1 A Box significantly protected TH+ neurons in Parkinson’s disease (PD) model mice and inhibited microglia activation and T cell infiltration including Th17 in the substantia nigra (SN). This study explored the mechanism of Th17 differentiation and how A Box inhibiting this process. Experimental approach: Clodronate liposomes were used to deplete the peripheral monocytes of mice, infused the labeled CD3+ T cells, and used immunoprecipitation to knock down the primary cells HMGB1 in vitro. At the same time, we combined the data of serum and blood cells of PD patients to study. Key results: Depletion of peripheral monocytes/macrophages reduced Th17 cell infiltration in the SN of MPTP mice and protected TH+ neurons. Co-culture experiments with knockdown of HMGB1 in primary cells showed that HMGB1, which induces monocyte/macrophage migration and infiltration into the SN, originates from neurons rather than glial cells. Data from MPP+-treated midbrain cell models and assays associated with adoptive transfer of CD3+ cells suggest that monocyte/macrophage and T cell migration into the SN is mediated by HMGB1/CXCL12-CXCR4. Co-immunoprecipitation and immunofluorescence confirmed that HMGB1 A Box bind to CXCR4 on T cells and macrophages, thereby competitively inhibiting their infiltration in SN. The HMGB1/CXCL12 complex is also present in the serum of PD patients. Conclusions and implications: HMGB1 A Box protects TH+ neurons by binding CXCR4 to inhibit the migration / infiltration of T cells and macrophages to SN mediated by HMGB1 / CXCL12 complex formed by neuron derived HMGB1.