Follicular Helper T (TFH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients
Natarajan Ayithan, Lydia Tang, Susanna K. Tan, Diana Chen, Jeffrey J. Wallin, Simon P. Fletcher, Shyam Kottilil, Bhawna Poonia
Abstract
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 naïve 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 naïve 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.