Systemic vaccination induces clonally diverse SIV-specific CD8+ T-cell populations in systemic and mucosal compartments

Abstract

An HIV-1 vaccine must elicit a clonally diverse virus-specific CD8+ T-cell response to contain mutant virus forms, and these responses must be present in mucosal tissues, which are the site of early HIV-1 replication. We show that systemic delivery of prototype vaccine vectors in rhesus monkeys induced SIV (simian immunodeficiency virus)-specific CD8+ T-cell responses in systemic and mucosal compartments with comparable clonal compositions. Although clonal sharing was maintained between the peripheral blood and lungs, the clonal constituents of the vaccine-induced CD8+ T-cell populations in the gastrointestinal mucosal tissues evolved away from the peripheral blood population. A phenotypic characterization indicated that the divergence was a consequence of differential trafficking and retention of the vaccine-induced cells in mucosal compartments. These findings highlight the circulation of vaccine-induced CD8+ T-cell populations between systemic and mucosal compartments and the importance of the expression of specific homing molecules for localization in mucosal tissues.

SIV-specific CD8+ T cells are clonotypically distinct across lymphoid and mucosal tissues

“…given time (43). In line with previous studies, we found a degree of clonotype sharing across anatomical compartments (25,26,44), which has likewise been reported in the context of influenza virus infection (45). However, we also identified anatomically unique clonotypes, most frequently in the peripheral blood and the GI tract.…”

“…Our data therefore suggest 2 mutually inclusive possibilities. The first is that individual CD8 + T cells are primed in situ and do not traffick extensively between anatomical compartments during chronic infection, implying that systemic vaccination may be required to elicit long-term immunity against HIV/ SIV (26). The second is that public clonotypes are more readily primed during the early stages of infection as a function of prevalence within the naive pool, which can be attributed to convergent recombination (48,49), and subsequently form highly stable tis-sue-resident populations, which are then more likely to be shared across sites of viral replication (27,50).…”

“…Recent work has identified discrete subsets of tissue-resident memory T cells, which occupy various epithelial, lymphoid, and mucosal sites (19)(20)(21)(22) and differ from circulating memory T cells (23), constitutively expressing the C-type lectin CD69 and lacking the lymph node (LN) homing markers CCR7 and CD62L (24). In line with this concept of localized adaptive immunity, previous studies have revealed a degree of clonotypic disparity between circulating and mucosal SIV-specific CD8 + T cells, both in the context of acute infection (25) and in response to vaccination (26). Similarly, tissue-resident CD8 + T cells isolated from the LNs of elite controllers in another study exhibited skewed clonotypic profiles relative to specificity-matched CD8 + T cells isolated from venous blood samples, whereas the corresponding CD69 -HIV-specific CD8 + T cells were clonotypically similar across the same anatomical compartments (27).…”

HIV Vaccines: A Brief Overview

“…In an additional study, systemic immunization with SIV Gag, either through a DNA/NYVAC or recombinant BCG/NYVAC prime‐boost strategy elicited potent and durable GI mucosal CD8+ responses. These cells were recruited from the systemic circulating pool early after vaccination and were mostly of the effector memory phenotype . Thus, strong cellular immunity may be achieved at the mucosa through systemic vaccination.…”

Optimization of Mucosal Responses after Intramuscular Immunization with Integrase Defective Lentiviral Vector

“…However, while the efficacy of intramuscular immunization with IDLV at inducing systemic antigen-specific immune responses after a single immunization is well established, no data are available concerning the mucosal immune responses. Some reports showed that in addition to systemic T cell response, intramuscular immunization was able to induce CD8+ T cell mediated antigen-specific immunity in gut mucosa, an important portal of entry of many infectious pathogens [31], [32].…”