Transcutaneous Administration of Imiquimod Promotes T and B Cell Differentiation into Effector Cells or Plasma Cells

Abstract

We are interested in promoting the development of transcutaneous immunization using microneedle technology and attempting to apply an adjuvant with transcutaneous immunization to improve the efficacy and reduce the amount of antigen and number of administrations needed. In this study, we collected basic information to help elucidate the mechanism responsible for the transcutaneous adjuvant activity of imiquimod (IMQ), which is a ligand of toll-like receptor (TLR) 7. In mouse groups administered ovalbumin (OVA), the OVA-specific IgG antibody titer of the IMQ-adjuvanted group was higher than that of the group administered OVA alone. No immune response bias due to transcutaneous IMQ administration was observed in terms of IgG1 (T helper cell [Th]2-type IgG subclass) and IgG2c (Th1-type IgG subclass) antibody titers. After the initial immunization, the IMQ-adjuvanted group showed increased migration of Langerhans cells to draining lymph nodes (dLNs) and active proliferation of OVA-specific CD4+ T cells. Transcutaneously administered IMQ did not affect the direction of CD4+ T cell differentiation, while promoted B cell activation and germinal center (GC) B cell differentiation. Immune staining revealed greater GC formation in the dLNs with the IMQ-adjuvanted group than in the OVA-alone group. In the secondary immune response, effector T cells increased in the dLNs and spleen, and effector memory T cells also increased in the spleen in the IMQ-adjuvanted group. In addition, our results suggested that the administration of IMQ enhanced B cell differentiation into plasma cells and GC B cells in the dLNs and spleen. In this study, we partially clarified the mechanism underlying the adjuvant activity of transcutaneously administered IMQ, which is required for the practical application of transcutaneous immunization with IMQ.

Germinal center versus extrafollicular responses in systemic autoimmunity: Who turns the blade on self?

“…In some of these, lupus results from direct variation of TLR7 gene dose, or enhanced nucleic acid sensing function. These models include BXSB Yaa mice that harbour a chromosomal segment duplication from X onto Y that contains TLR7 ( Pisitkun et al, 2006 ; Soni et al, 2014 ) , Tlr7 transgenic (tg) mice ( Walsh et al, 2012 ), TLR7-agonist (imiquimod) induced lupus ( Hirobe et al, 2022 ; Voss et al, 2022 ), and kika mice that carry a TLR7 gain-of-function variant found in a girl with SLE ( Brown et al, 2022 ). In another group of lupus models in which Tlr7 gene expression is intact, disease pathogenesis is also dependent on TLR7 signaling.…”