Abstract
Intracellular pathogens are capable of inducing vigorous CD8+ T cell responses. However, we do not entirely understand the factors driving the generation of large pools of highly protective memory CD8+ T cells. Here, we studied the generation of endogenous ovalbumin-specific memory CD8+ T cells following infection with recombinant vesicular stomatitis virus (VSV) and Listeria monocytogenes (LM). VSV infection resulted in the generation of a large ovalbumin-specific memory CD8+ T cell population, which provided minimal protective immunity that waned with time. In contrast, the CD8+ T cell population of LM-ova provided protective immunity and remained stable with time. Agonistic CD40 stimulation during CD8+ T cell priming in response to VSV infection enabled the resultant memory CD8+ T cell population to provide strong protective immunity against secondary infection. Enhanced protective immunity by agonistic anti-CD40 was dependent on CD70. Agonistic anti-CD40 not only enhanced the size of the resultant memory CD8+ T cell population, but enhanced their polyfunctionality and sensitivity to antigen. Our data suggest that immunomodulation of CD40 signaling may be a key adjuvant to enhance CD8+ T cell response during development of VSV vaccine strategies.
Highlights
The goal of any vaccine is to provide long-term protective immunity against the target antigen
Our previous data indicated that infection with either vesicular stomatitis virus (VSV)-ova or Listeria monocytogenes (LM)-ova could induce robust memory CD8+ T cell responses capable of significant re-expansion, but protective immunity was not measured [14]
Naıve C57BL/6 or ‘‘memory’’ mice that were previously infected (.4 months) with either VSV-ova or LMova were challenged with 56105 colony-forming units (CFU) of LM-ova
Summary
The goal of any vaccine is to provide long-term protective immunity against the target antigen. Effective T cell vaccines are highly desirable for prophylaxis and immunotherapy of chronic infections and tumors [1]. T cell responses can be divided into four distinct phases: activation, expansion, contraction, and memory. The activation of a CD8+ T cell response is initiated by peptide:MHC presentation to cognate naıve T cells by professional antigen-presenting cells. CD8+ T cells undergo a rapid expansion whereby they increase in numbers by up to 50,000-fold [2,3,4]. Activated CD8+ T cells undergo a dramatic genetic reprogramming, resulting in expression of their cytotoxic effector program [5]. Activation and genetic reprogramming of naıve CD8+ T cells to generate effector and memory T cells requires three types of signals: 1) TCR engagement with cognate antigen presented by MHC, 2)
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