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| Status |
Public on Jun 16, 2015 |
| Title |
Quiescence of Memory CD8+ T Cells Is Mediated by Regulatory T Cells through Inhibitory Receptor CTLA-4 |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection. However, despite heightened readiness to respond, memory cells exist in a functionally quiescent state. The paradigm is that memory cells remain inactive due to lack of TCR stimuli. Here we report a unique role of Tregs in orchestrating memory quiescence by inhibiting effector and proliferation programs through CTLA-4. Loss of Tregs resulted in activation of genome-wide transcriptional programs characteristic of potent effectors, and both developing and established memory quickly reverted to a terminally differentiated (KLRG-1hi/IL-7R±lo/GzmBhi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality and protective efficacy. CTLA-4, an inhibitory receptor overexpressed on Tregs, functionally replaced Tregs in trans to rescue Treg-less memory defects and restore homeostasis of secondary mediators as well. These studies present CD28-CTLA-4-CD80/CD86 axis as a novel target to potentially accelerate vaccine-induced immunity and improve T-cell memory quality in current cancer immunotherapies proposing transient Treg-depletion.
We used microarray analysis to detail the global programming of gene expression in LCMV GP33-specific CD8 T cells differentiated in the presence or absence of regulatory T cells
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| Overall design |
Differentiation of memory CD8 T cells entails a progressive transition of highly activated effector program to a quiescent memory program. A key question in the field is to understand the factors that aid in the differentiation of memory cells from effector cells. It is a generally accepted paradigm that effector cells transition to a memory state by default after antigen clearance, since TCR stimuli is the key driver of effector programs in CD8 T cells. We hypothesized that the effector to memory transition of CD8 T cells involves active immunological brakes through regulatory T cells (Tregs) that allow the highly activated effector cells to convert into quiescent memory cells. To address this hypothesis, we used FoxP3-DTR mice to deplete Tregs during the window following antigen clearance, during which the effector CD8 T cells convert to long-lived memory cells. To get a deeper understanding of the global transcriptome of CD8 T cells as they transition from an effector to a memory state, we isolated and arrayed the antigen-specific CD8 T cells at day 16 post-infection that have experienced the transitional environment with and without the presence of Tregs.
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| Contributor(s) |
Kalia V, Sarkar S |
| Citation(s) |
26084026 |
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| Submission date |
Apr 06, 2015 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Surojit Sarkar |
| Organization name |
University of Washington School of Medicine
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| Department |
Department of Pediatrics and Laboratory Medicine
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| Lab |
Laboratory of T Cell Immunity to Pathogens and Cancer
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| Street address |
1100 Olive Way, Suite 100
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| City |
Seattle |
| State/province |
WA |
| ZIP/Postal code |
98101 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (6)
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| GSM1650236 |
Day 16 post-LCMV infection (+Treg), biological rep1 |
| GSM1650237 |
Day 16 post-LCMV infection (+Treg), biological rep2 |
| GSM1650238 |
Day 16 post-LCMV infection (+Treg), biological rep3 |
| GSM1650239 |
Day 16 post-LCMV infection (-Treg D8-16), biological rep1 |
| GSM1650240 |
Day 16 post-LCMV infection (-Treg D8-16), biological rep2 |
| GSM1650241 |
Day 16 post-LCMV infection (-Treg D8-16), biological rep3 |
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| Relations |
| BioProject |
PRJNA280396 |
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