Critical Role for Activation of Antigen-Presenting Cells in Priming of Cytotoxic T Cell Responses After Vaccination with Virus-Like Particles

Abstract

Virus-like particles (VLPs) are known to induce strong Ab responses in the absence of adjuvants. In addition, VLPs are able to prime CTL responses in vivo. To study the efficiency of this latter process, we fused peptide p33 derived from lymphocytic choriomeningitis virus to the hepatitis B core Ag, which spontaneously assembles into VLPs (p33-VLPs). These p33-VLPs were efficiently processed in vitro and in vivo for MHC class I presentation. Nevertheless, p33-VLPs induced weak CTL responses that failed to mediate effective protection from viral challenge. However, if APCs were activated concomitantly in vivo using either anti-CD40 Abs or CpG oligonucleotides, the CTL responses induced were fully protective against infection with lymphocytic choriomeningitis virus or recombinant vaccinia virus. Moreover, these CTL responses were comparable to responses generally induced by live vaccines, because they could be measured in primary ex vivo 51Cr release assays. Thus, while VLPs alone are inefficient at inducing CTL responses, they become very powerful vaccines if applied together with substances that activate APCs.

Improving the therapeutic index of CpG oligodeoxynucleotides by intralymphatic administration

“…However, a major drawback of CpG is their relatively high toxicity at the doses required to stimulate the innate and adaptive immune systems, when delivered via conventional parenteral means [13,14,21]. It would therefore be helpful to develop an immunization strategy that is able to reduce the side Fig.…”

“…CpG treatment promotes Th1 immune responses, which can be therapeutic in allergy and asthma and enhance resistance to various viral, bacterial and protozoan infections [5,[9][10][11][12]. The combination of antigens with CpG was shown to induce maturation of professional antigen-presenting cells (APC), such as DC and macrophages, resulting in effective display of resulting epitopes on MHC class I and class II molecules, with subsequent activation and expansion of antigen-specific CD4 and CD8 T lymphocytes [10,11,[13][14][15][16]. Importantly, CpG ODN were shown to stimulate APC to a level allowing cross-priming of CD8 + T cells [13][14][15].…”

“…The combination of antigens with CpG was shown to induce maturation of professional antigen-presenting cells (APC), such as DC and macrophages, resulting in effective display of resulting epitopes on MHC class I and class II molecules, with subsequent activation and expansion of antigen-specific CD4 and CD8 T lymphocytes [10,11,[13][14][15][16]. Importantly, CpG ODN were shown to stimulate APC to a level allowing cross-priming of CD8 + T cells [13][14][15]. These results illustrate the potential of CpG as adjuvant in vaccines against infectious disease, allergy and cancer [3], reflected in the several ongoing clinical trials [17].…”

Innate signaling regulates cross‐priming at the level of DC licensing and not antigen presentation

“…Peptide p13 and p33 were coupled to the VLP Qb as described previously [4]. Free peptide was removed by dialysis against HEPES (pH 7.2).…”

“…Since not all pathogens directly infect APC, it is necessary that APC are able to internalize exogenous antigens and present them on MHC class I molecules for CD8 1 T-cell recognition, a process known as cross-presentation [1][2][3]. Such cross-presented antigens may make an important contribution to the induction of CTL responses, in particular for non-replicating antigens, such as virus-like particles (VLP) [4]. The main cell types involved in cross-presentation are professional APC, such as DC [5,6] as well as macrophages [7,8] but not B cells [9].…”