Intranasal lipopeptide primes lung‐resident memory CD8⁺ T cells for long‐term pulmonary protection against influenza

Abstract

The longevity of the influenza virus-specific CD8 + T cell response following intranasal delivery of a synthetic lipopeptide was investigated and the characteristics and location of the cells associated with viral clearance examined. The lipopeptide, incorporating an epitope for CD8 + T cells and another for CD4 + T cells with the lipid moiety S-[2,3-bis(palmitoyloxy)propyl]cysteine (Pam2Cys) attached, induced potent and long-lived pulmonary protection. Both the lipopeptide and its largely unprotective non-lipidated counterpart elicited comparable numbers of CD8 + T cells in the spleen, which was the main location of the memory pool. However, the lipopeptide, unlike the non-lipidated peptide, also induced a substantial memory population that remained in the lungs and was rapidly activated upon viral challenge months later. These lipopeptide-induced lung-resident CD8 + T cells were also very similar in number and IFN-c-secreting potential to those induced by prior exposure to the virus itself and are likely mediators of initial viral clearance prior to recruitment from the expanding lymph node T cell pool. Significant clearing responses were demonstrated as late as 9 months post-lipopeptide vaccination. This study shows that CD8 + T cells primed by the lipopeptide are not only long-lived but can take up residence in the lung where they are important early mediators of pulmonary protection.

Seasonal influenza infection and live vaccine prime for a response to the 2009 pandemic H1N1 vaccine

“…Following a heterologous infection, there was an expansion of these CD8 + T cells in lungs with immediate effector functions such as the production of antiviral cytokines. The contribution of CD8 + T cells to viral clearance from the lungs has been demonstrated in a number of studies, using adoptive transfer, depletion of CD8 + T cells, or CTL-inducing vaccines (34)(35)(36)(37)(38)(39). CD8 + T cells can mediate viral clearance from the respiratory tract by lysing target cells following exocytosis of granules containing perforin and granzymes (40).…”

Synthetic Peptide Vaccines

“…Currently adjuvants synthesized on the basis of pathogen-associated unique highly conserved molecular structures are widely used; they do not have analogues in (Düesberg et al, 2002;Chua et al, 2007;Jackson et al, 2004;Deliyannis et al, 2006), a synthetic analogue of the lipid fragment of macrophage activating lipopeptide-2 isolated from Mycoplasma fermentans membranes is one of such structures. Pam 2 Cys has been used in some candidate synthetic peptide vaccines against hepatitis C virus; these vaccines consist of cytotoxic HLA-A2-specific Tepitope of the HCV NS5B protein or of highly immunogenic hypervariable region 1 of HCV E2 envelope protein and a foreign CD4+ T-helper epitope (Engler et al, 2004;Torresi et al, 2007;Chua et al, 2008).…”

A Modular Approach to Assembly of Totally Synthetic Self-adjuvanting Lipopeptide-based Vaccines Allows Conformational Epitope Building

“…The self-adjuvanting properties of lipopeptides abolish the need for additional, potentially toxic adjuvants in vaccine preparations because the lipid moiety Pam2Cys provides the required stimulatory signals to the immune system through engagement of toll-like receptors present on dendritic cells. This form of vaccine candidate is capable not only of inducing humoral and cell-mediated immunity depending on the nature of the target epitope(s) but also mucosal immunity if administered intranasally, a property that potentially removes the requirement for needle vaccine delivery (5)(6)(7)(8)(9).…”

“…are able to elicit strong CTL responses, reduce viral loads (7,8,20,29), and protect mice from lethal viral challenge (30).…”