Abstract
CD8+ cytotoxic T lymphocytes (CTLs) play a major role in defense against intracellular pathogens. During development, antigen-presenting cells secrete innate cytokines such as IL-12 and IFN-α, which drive CTL differentiation into diverse populations of effector and long-lived memory cells. Using whole transcriptome analyses, the serine/threonine protein kinase Tpl2/MAP3K8 was found to be induced by IL-12 and selectively expressed by effector memory (TEM) CTLs. Tpl2 regulates various inflammatory pathways by activating the ERK mediated MAP kinase pathway in innate immune cells such as macrophages and dendritic cells. In this study, we found that a specific small molecule Tpl2 inhibitor blocked IFN-γ and TNF-α secretion as well as cytolytic activity of human CTLs. This pathway was specific for human effector CTLs, as the Tpl2 inhibitor did not block IFN-γ and TNF-α secretion from murine effector CTLs. Further, IL-12 failed to induce expression of Tpl2 in murine CTLs, and Tpl2 deficient murine CTLs did not exhibit any functional deficiency either in vitro or in vivo in response to L. monocytogenes infection. In summary, we identified a species-specific role for Tpl2 in effector function of human CTLs, which plays a major role in adaptive immune responses to intracellular pathogens and tumors.
Highlights
CD8+ cytotoxic T lymphocytes (CTLs) regulate immunity to intracellular infections and tumors by secreting pro-inflammatory cytokines and killing infected cells
We previously demonstrated that CD8+ CCR7luCXCR3hi T cells isolated from human peripheral blood contain TEM CTLs that display robust effector function in the absence of additional cytokine stimuli [8]
We further tested the ability of WT and Tpl22/2 CD8+ T cells to differentiate into primary effector cells in vitro in response to IL-12 priming conditions. Consistent with their ability to develop into primary effectors in vivo (Figure 3) we found that CTLs from Tpl2+/+, Tpl2+/2, and Tpl22/2 mice were competent in their ability to secrete either IFN-cor TNF-a in response to IL-12 in vitro (Figure 4B)
Summary
CD8+ cytotoxic T lymphocytes (CTLs) regulate immunity to intracellular infections and tumors by secreting pro-inflammatory cytokines and killing infected cells. These functions are acquired by naıve CTLs during their initial priming in response to both antigen recognition and innate cytokines [1]. Some of the IL12 regulated genes were stably expressed within the TEM CTLs ex vivo when compared to the TN+CM CTLs [8]. Within this gene signature we identified a MAP kinase pathway intermediate, Tpl, to be differentially regulated by IL-12. The goal of this study is to test the role of Tpl in effector function of human CD8+ T cells
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