Follicular Helper T (T-Fh) Cell Targeting By Tlr8 Signaling For Improving Hbsag-Specific B Cell Response In Chronic Hepatitis B Patients

Identifying signaling pathways that induce B cell response can aid functional cure strategies for chronic hepatitis B infection (CHB). TLR8 activation with ssRNA was shown to enhance follicular helper T cell (T-FH) function leading to improved B cell responses in vitro. We investigated whether this mechanism can rescue an exhausted immune response in CHB infection. Effect of TLR8 agonism on supporting cytokines and T-FH and B cells were evaluated using ex vivo and in vitro assays. The ability of an oral TLR8 agonist to promote T-FH and B cell response was tested in samples from phase 1b clinical trial. TLR8 agonism induced T-FH polarizing cytokine IL-12 in monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) from CHB patients with TLR8 agonists induced cytokine IL-21 by T-FH cells with enhanced IL-21(+)BCL-6(+) and ICOS+BCL-6(+) co-expression. Mechanistically, incubation of isolated naive CD4(+) T cells with TLR8 triggered monocytes resulted in their differentiation into IL-21(+)ICOS(+)BCL-6(+) T-FH in an IL-12 dependent manner. Furthermore, co-culture of these IL-21 producing T-FH with autologous naive B cells led to enhanced memory (CD19(+)CD27(+)) and plasma B cell generation (CD19(+)CD27(++)CD38(+)) and IgG production. Importantly, in T-FH from CHB patients treated with an oral TLR8 agonist, HBsAg-specific BCL-6, ICOS, IL-21 and CD40L expression and rescue of defective activation induced marker (AIM) response along with partial restoration of HBsAg-specific B cell ELISPOT response was evident. TLR8 agonism can thus enhance HBV-specific B cell responses in CHB patients by improving monocyte-mediated T-FH function and may play a role in achieving HBV functional cure.