htlv-1-specific CD4+ T Cell Contribution to Neuroinflammation in htlv-1-associated Myelopathy

Abstract Text: Human T cell leukaemia virus type 1 (HTLV-1) is a retrovirus that infects 10-20 million people. Most infected people remain asymptomatic carriers (ACs), while 2-5% of HTLV-1 carriers develop adult T-cell leukaemia and another 2-5% develop inflammatory diseases including HTLV-1-associated myelopathy (HAM). HAM is an inflammatory disease of the CNS characterised by chronic inflammatory demyelination that resembles progressive spinal forms of multiple sclerosis, and for which no curative treatments are available. Individuals with higher HTLV-1 proviral loads (PVL) are at an increased risk for HAM. CD4+ T cells carry 95% of the HTLV-1 PVL and predominate in the early CNS lesions, suggesting the involvement of CD4+ T cells in HAM pathogenesis. However, the contribution of HTLV-1-specific CD4+ T cells to disease pathogenesis is unknown. By performing RNA-seq analysis of HTLV-1-specific CD4+ T cells from HAM patients and ACs, we identified over 500 differentially expressed genes in HAM patients when compared to high PVL ACs including upregulation of EOMES, SEMA4A, IL17RC, and the downregulation of IL1RN, which we have confirmed by flow cytometry. Pathway enrichment analysis showed that HAM patients upregulate signalling through Rho GTPases, have increased NRAGE death signalling through JNK, and increased signalling by p75NTR. These pathways modulate CNS resident cells including microglia and astrocytes, which we have confirmed in ex vivo co-culture experiments with HTLV-1-specific CD4+ T cells. Our results on the contribution of CD4+ T cells to HAM pathogenesis has identified novel potential targets for HAM treatment.