A Prime-Pull-Amplify Vaccination Strategy To Maximize Induction of Circulating and Genital-Resident Intraepithelial CD8⁺ Memory T Cells

Abstract

Recent insight into the mechanisms of induction of tissue-resident memory (T_RM) CD8⁺ T cells (CD8⁺ T_RM) enables the development of novel vaccine strategies against sexually transmitted infections. To maximize both systemic and genital intraepithelial CD8⁺ T cells against vaccine Ags, we assessed combinations of i.m. and intravaginal routes in heterologous prime-boost immunization regimens with unrelated viral vectors. Only i.m. prime followed by intravaginal boost induced concomitant strong systemic and intraepithelial genital-resident CD8⁺ T cell responses. Intravaginal boost with vectors expressing vaccine Ags was far superior to intravaginal instillation of CXCR3 chemokine receptor ligands or TLR 3, 7, and 9 agonists to recruit and increase the pool of cervicovaginal CD8⁺ T_RM. Transient Ag presentation increased trafficking of cognate and bystander circulating activated, but not naive, CD8⁺ T cells into the genital tract and induced in situ proliferation and differentiation of cognate CD8⁺ T_RM. Secondary genital CD8⁺ T_RM were induced in the absence of CD4⁺ T cell help and shared a similar TCR repertoire with systemic CD8⁺ T cells. This prime-pull-amplify approach elicited systemic and genital CD8⁺ T cell responses against high-risk human papillomavirus type 16 E7 oncoprotein and conferred CD8-mediated protection to a vaccinia virus genital challenge. These results underscore the importance of the delivery route of nonreplicating vectors in prime-boost immunization to shape the tissue distribution of CD8⁺ T cell responses. In this context, the importance of local Ag presentation to elicit genital CD8⁺ T_RM provides a rationale to develop novel vaccines against sexually transmitted infections and to treat human papillomavirus neoplasia.