Effects of Signal 3 during CD8 T cell priming: Bystander production of IL-12 enhances effector T cell expansion but promotes terminal differentiation

Cui, Weiguo; Joshi, Nikhil S.; Jiang, Aimin; Kaech, Susan M.

doi:10.1016/j.vaccine.2009.01.088

Cited by 110 publications

(148 citation statements)

References 45 publications

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“…It is well established that three signals are necessary for the activation of naïve CD8 + T cells: (i) TCR stimulation, (ii) costimulation, and (iii) inflammatory cytokines (15), but how variations in these signals may orchestrate effector and memory heterogeneity is not clear. Interestingly, alterations in the amount of antigenic exposure do not seem to skew effector cell differentiation, but the inflammatory milieu is able to alter the SLEC/MPEC ratio (12,14,16).…”

Section: Both Cd4mentioning

confidence: 99%

“…Although earlier work demonstrated that TCR or cytokine signaling alone were insufficient to up-regulate KLRG1 on T cells (39), recent work has shown that IL-12 signaling in the antigen-specific CD8 + T cells is important for SLEC differentiation and this process is T-bet mediated (12). Furthermore, inflammatory and IL-12 signaling events are temporally linked with TCR engagement (16). The transcription factor Blimp1 has been found to be important in the generation of SLEC (40,41).…”

Section: Cd40 Independent But Required Cd4mentioning

confidence: 99%

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CD4 ⁺ T cell regulation of CD25 expression controls development of short-lived effector CD8 ⁺ T cells in primary and secondary responses

Obar

Molloy

Jellison

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

170

210

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Both CD4+ T cell help and IL-2 have been postulated to "program" activated CD8 + T cells for memory cell development. However, the linkage between these two signals has not been well elucidated. Here we have studied effector and memory CD8 + T cell differentiation following infection with three pathogens (Listeria monocytogenes, vesicular stomatitis virus, and vaccinia virus) in the absence of both CD4 + T cells and IL-2 signaling. We found that expression of CD25 on antigen-specific CD8 + T cells peaked 3-4 days after initial priming and was dependent on CD4 + T cell help, likely through a CD28:CD80/86 mediated pathway. CD4 + T cell or CD25-deficiency led to normal early effector CD8 + T cell differentiation, but a subsequent lack of accumulation of CD8 + T cells resulting in overall decreased memory cell generation. Interestingly, in both primary and recall responses KLRG1 high CD127 low short-lived effector cells were drastically diminished in the absence of IL-2 signaling, although memory precursors remained intact. In contrast to previous reports, upon secondary antigen encounter CD25-deficient CD8 + T cells were capable of undergoing robust expansion, but short-lived effector development was again impaired. Thus, these results demonstrated that CD4 + T cell help and IL-2 signaling were linked via CD25 up-regulation, which controls the expansion and differentiation of antigen-specific effector CD8 + T cells, rather than "programming" memory cell traits.infection | memory

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Section: Both Cd4mentioning

confidence: 99%

Section: Cd40 Independent But Required Cd4mentioning

confidence: 99%

CD4 ⁺ T cell regulation of CD25 expression controls development of short-lived effector CD8 ⁺ T cells in primary and secondary responses

Obar

Molloy

Jellison

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

170

210

View full text Add to dashboard Cite

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“…IFN-g is required to upregulate T-bet in CD8 + T cells in an indirect manner upon virus infection (12,41). We wondered whether the increased expression of T-bet in Roquin san/san mice is a consequence of excessive IFN-g. To assess this, we measured Tbet mean fluorescence intensity (MFI) in naive (CD44 lo ) CD8 + T cells and SLEC-like cells from Roquin san/san mice deficient or not in IFN-gR1.…”

Section: T-bet Reduction Delays the Onset Of Diabetesmentioning

confidence: 99%

Breakdown in Repression of IFN-γ mRNA Leads to Accumulation of Self-Reactive Effector CD8+ T Cells

Chang

Lee

et al. 2012

The Journal of Immunology

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Tight regulation of virus-induced cytotoxic effector CD8+ T cells is essential to prevent immunopathology. Naturally occurring effector CD8+ T cells, with a KLRG1hi CD62Llo phenotype typical of short-lived effector CD8+ T cells (SLECs), can be found in increased numbers in autoimmune-prone mice, most notably in mice homozygous for the san allele of Roquin. These SLEC-like cells were able to trigger autoimmune diabetes in a susceptible background. When Roquin is mutated (Roquinsan), effector CD8+ T cells accumulate in a cell-autonomous manner, most prominently as SLEC-like effectors. Excessive IFN-γ promotes the accumulation of SLEC-like cells, increases their T-bet expression, and enhances their granzyme B production in vivo. We show that overexpression of IFN-γ was caused by failed posttranscriptional repression of Ifng mRNA. This study identifies a novel mechanism that prevents accumulation of self-reactive cytotoxic effectors, highlighting the importance of regulating Ifng mRNA stability to maintain CD8+ T cell homeostasis and prevent CD8-mediated autoimmunity.

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“…2B). Interestingly, during this time, most cells retained high levels of CD127 (IL-7R), which is generally down-regulated upon CD8 T-cell activation (30) and did not up-regulate KLRG1, whose induction is linked to terminal differentiation (31,32).…”

Section: Endogenous Naïve Cd8 T Cells Undergo Robust Expansion But Notmentioning

confidence: 99%

Distinct mechanisms mediate naïve and memory CD8 T-cell tolerance

Jellison

Turner

Blair

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells. Induction of antigen in dendritic cells resulted in substantial expansion and maintenance of endogenous antigen-specific CD8 T cells. The self-reactive cells initially exhibited effector activity but eventually became unresponsive. Upon antigen removal, the antigen-specific population waned, resulting in development of a selfspecific memory subset that recalled to subsequent challenge. In striking contrast to naïve CD8 T cells, preexisting antigen-specific memory CD8 T cells failed to expand after antigen induction and essentially ignored the antigen despite widespread expression by dendritic cells. The inclusion of inflammatory signals partially overcame memory CD8 T-cell ignorance of self-antigen. Thus, peripheral CD8 T-cell tolerance for naïve CD8 T cells depended on the continuous presence of antigen, whereas memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation.autoimmunity | AIRE | transgenic mouse

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Effects of Signal 3 during CD8 T cell priming: Bystander production of IL-12 enhances effector T cell expansion but promotes terminal differentiation

Cited by 110 publications

References 45 publications

CD4 ⁺ T cell regulation of CD25 expression controls development of short-lived effector CD8 ⁺ T cells in primary and secondary responses

CD4 ⁺ T cell regulation of CD25 expression controls development of short-lived effector CD8 ⁺ T cells in primary and secondary responses

Breakdown in Repression of IFN-γ mRNA Leads to Accumulation of Self-Reactive Effector CD8+ T Cells

Distinct mechanisms mediate naïve and memory CD8 T-cell tolerance

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Effects of Signal 3 during CD8 T cell priming: Bystander production of IL-12 enhances effector T cell expansion but promotes terminal differentiation

Cited by 110 publications

References 45 publications

CD4 + T cell regulation of CD25 expression controls development of short-lived effector CD8 + T cells in primary and secondary responses

CD4 + T cell regulation of CD25 expression controls development of short-lived effector CD8 + T cells in primary and secondary responses

Breakdown in Repression of IFN-γ mRNA Leads to Accumulation of Self-Reactive Effector CD8+ T Cells

Distinct mechanisms mediate naïve and memory CD8 T-cell tolerance

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CD4 ⁺ T cell regulation of CD25 expression controls development of short-lived effector CD8 ⁺ T cells in primary and secondary responses

CD4 ⁺ T cell regulation of CD25 expression controls development of short-lived effector CD8 ⁺ T cells in primary and secondary responses