# Defining post-transcriptional mechanisms that control CD8 T cell longevity, proliferation and differentiation

> **NIH NIH R01** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2022 · $540,675

## Abstract

PROJECT SUMMARY
CD8 T cells play a critical role in the elimination of infected and cancerous host cells. The success of these
immune responses depends on the proper maintenance (survival and proliferation) and precise differentiation of
CD8 T cells. Upon antigen stimulation, activated antigen-specific CD8 T cells undergo clonal expansion and
differentiate into effector lymphocytes with cytolytic function. Although the majority of effector cells die after
antigen clearance, a few antigen-specific cells survive and form long-lived protective memory CD8 T cells.
However, during chronic infection and cancer, the immune response is often compromised: CD8 T cells exhibit
defects in survival and proliferation, fail to form memory cells and instead are diverted to differentiate into
exhausted cells which are characterized by the loss of effector function. Thus, it is of utmost importance to
understand the underlying mechanisms that regulate the maintenance and differentiation of CD8 T cells. We
have already demonstrated that let-7-mediated posttranscriptional mechanism controls the differentiation and
function of effector T cells. Furthermore, our preliminary results suggest that modulation of let-7 levels have a
profound impact on the maintenance of T cells, memory formation and diversion into exhaustion. To investigate
the molecular mechanisms of let-7 regulation in CD8 T cells we propose the following aims:
Aim-1 will determine the molecular basis of let-7-mediated effects on CD8 T cell maintenance: bcl-2-dependent
survival and cdc34-driven proliferation. Aim-2 will dissect let-7-mediated mechanisms that guide CD8 T cell
differentiation: Eomes-dependent and Eomes-independent molecular programs. To address these aims we will
analyze the maintenance and differentiation of CD8 T cells with different levels of let-7 microRNAs into effector,
memory and exhausted T lymphocytes using infection and tumor models. We expect to identify novel
posttranscriptional mechanisms that regulate the outcome of CD8 T cell-mediated immune responses. It is
anticipated that these experiments will define let-7 as a new therapeutic target.

## Key facts

- **NIH application ID:** 10308478
- **Project number:** 5R01AI146188-03
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** Leonid Pobezinskiy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $540,675
- **Award type:** 5
- **Project period:** 2019-12-06 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308478

## Citation

> US National Institutes of Health, RePORTER application 10308478, Defining post-transcriptional mechanisms that control CD8 T cell longevity, proliferation and differentiation (5R01AI146188-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10308478. Licensed CC0.

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