Abstract
Memory CD8+ T lymphocytes play a central role in protective immunity. In attempt to increase the frequencies of memory CD8+ T cells, repeated immunizations with viral vectors are regularly explored. Lentivectors have emerged as a powerful vaccine modality with relatively low pre-existing and anti-vector immunity, thus, thought to be ideal for boosting memory T cells. Nevertheless, we found that lentivectors elicited diminished secondary T-cell responses that did not exceed those obtained by priming. This was not due to the presence of anti-vector immunity, as limited secondary responses were also observed following heterologous prime-boost immunizations. By dissecting the mechanisms involved in this process, we demonstrate that lentivectors trigger exceptionally slow kinetics of antigen expression, while optimal activation of lentivector-induced T cells relays on durable expression of the antigen. These qualities hamper secondary responses, since lentivector-encoded antigen is rapidly cleared by primary cytotoxic T cells that limit its presentation by dendritic cells. Indeed, blocking antigen clearance by cytotoxic T cells via FTY720 treatment, fully restored antigen presentation. Taken together, while low antigen expression is expected during secondary immunization with any vaccine vector, our results reveal that the intrinsic delayed expression kinetics of lentiviral-encoded antigen, further dampens secondary CD8+ T-cell expansion.
Highlights
Since the protective capacity of memory CD8+ T cells is generally a function of their absolute number in the host, approaches to amplify their frequencies are constantly examined [1]
To further evaluate the issue of lentivectorspecific immunity, we replaced the Vesicular stomatitis virus glycoprotein (VSV-G) envelope protein in our boosting vector with the envelope of the amphotropic murine leukemia virus, as it was shown that anti-vector immunity is generated mostly against the envelope protein [6]
We first showed that lentivectors harboring the amphotropic murine leukemia virus (Ampho) envelope are very immunogenic, priming comparable levels of naıve CD8+ T cells to those achieved by VSV-G containing vectors (Fig. 1C)
Summary
Since the protective capacity of memory CD8+ T cells is generally a function of their absolute number in the host, approaches to amplify their frequencies are constantly examined [1]. Viral vectors vary in their capacity to expand memory CD8+ T cells, partly, due to the presence of vectorspecific immune responses [3] Such variations exist even in the absence of anti-vector immunity [4]. As for the immunogenicity of lentivectors, recent studies have shown their capacity to elicit robust and sustained T-cell responses that can protect against cancers and infectious diseases [7,8,9]. These imply that lentivectors could be an ideal vaccine modality to boost CD8+ T cells in a setting of heterologous prime-boost immunization. It was thought that lentivectors can be used in multiple rounds of immunizations in order to augment ‘‘primary’’ immune responses as in the case of DNA vaccination [10]
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