Pathogen-Induced Inflammatory Environment Controls Effector and Memory CD8+ T Cell Differentiation

Abstract

In response to infection CD8+ T cells integrate multiple signals and undergo an exponential increase in cell numbers. Simultaneously, a dynamic differentiation process occurs, resulting in the formation of short-lived (SLEC; CD127lowKLRG1high) and memory-precursor (MPEC; CD127highKLRG1low) effector cells from an early-effector cell (EEC) that is CD127lowKLRG1low in phenotype. CD8+ T cell differentiation during vesicular stomatitis virus (VSV) infection differed significantly than during Listeria monocytogenes infection with a substantial reduction in EEC differentiation into SLECs. SLEC generationwas dependent on Ebi3 expression. Furthermore, SLEC differentiation during VSV infection wasenhanced by administration ofCpG-DNA, through an IL-12 dependent mechanism. Moreover, CpG-DNAtreatment enhanced effector CD8+ T cell functionality and memory subset distribution, but in an IL-12 independent manner. Population dynamics were dramatically different during secondary CD8+ T cell responses, with a much greater accumulation of SLECs and the appearance of a significant number of CD127highKLRG1highmemory cells, both of which were intrinsic to the memory CD8+ T cell. These subsets persisted for several months, but were less effective in recall than MPECs. Thus, our data shed light on how varying the context of T cell priming alters downstream effector and memory CD8+ T cell differentiation.

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

“…Although suggested in a prior study, transfers of purified populations of effector subsets were not performed making it difficult to determine whether conversion had occurred. 12 However, in other work, transferred WT KLRG1 hi cells did not revert to KLRG1 lo cells; 1,41,42 and here the numbers of KLRG1 lo CD127 hi cells in Bim À / À mice did not increase in proportion to the loss of KLRG1 hi C-D127 lo cells, arguing against conversion. More work is needed to determine if, in the absence of death, some KLRG1 hi CD127 lo cells convert to KLRG1 lo CD127 hi cells.…”

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

“…1C, 1D). However, an increase in early effector cells (EECs; KLRG1 low and CD127 low ), the precursors of both SLECs and MPECs (40), is also observed in Notch D/D mice (Fig. 1C, 1D).…”

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

“…IL-12 and IFN-γ can further influence CD4 T-cell fate (19,20), and malaria-induced IFN-γ has been implicated in regulating the contraction of Plasmodium-specific CD4 T cells (12,16). Although the effects of IL-12 and IFN-γ on T-cell development and survival are well characterized in many infection models (11,15,21,22), they have not been investigated thoroughly during malaria. Because IL-12 regulates IFN-γ pro-duction, we were interested in studying the effects of elevated IFN-γ and IL-12 levels on Plasmodium-specific CD4 T-cell expansion and function during blood-stage malaria.…”

“…Although inflammatory cytokines such as TNF-α and IFN-γ act to control the malaria parasite burden (13,14), high levels of inflammation also promote the development of terminally differentiated effector cells. In viral infections, elevated expression of IL-12 favors the development of responding T cells into short-lived, terminal effector cells rather than memory precursor effector cells (11,15); however less is known about the effects of inflammatory cytokines on the development of memory T cells during Plasmodium infections. There is evidence that during blood-stage Plasmodium infection IFN-γ is detrimental to the survival of Plasmodium-specific CD4 T cells by regulating its contraction phase (12,16).…”