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.
Intracellular pathogens are capable of inducing vigorous CD8 T cell responses. However, it is unclear whether all memory CD8 T cell populations are capable of providing robust protective immunity against secondary infection. While both vesicular stomatitis virus (VSV) and Listeria monocytogenes infection result in the generation of large memory CD8 T cell populations that are capable of rapid secondary expansion, only memory cells induced by L. monocytogenes were protective against secondary infection. The lack of protective immunity after VSV priming correlated with expression of PD-1 on memory CD8 T cells. Importantly, mAb blockade of PD-1 at the time of re-challenge enhanced the ability of the VSV-induced memory CD8 T cell population to provide protective immunity. Moreover, overt activation of CD40, but not TLR9, signaling during priming enables the memory CD8 T cell population to provide strong protective immunity. CD40 signaling appears to alter the programming of the CD8 T cell response induced by VSV infection. Our data demonstrate that not all vaccine vectors are equal in their ability to generate highly protective memory CD8 T cell populations, even though they may generate memory population capable of undergoing robust secondary expansion. Thus, understanding how the CD40 signaling pathways regulate the generation of highly protective memory CD8 T cells will provide key insights into memory CD8 T cell biology and vaccine development.
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