# Determinants of differentiation and maintenance of PD-1+ CD8 T cells

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $652,855

## Abstract

SUMMARY
Recent findings identified that Programmed Cell Death (PD)-1+ CD8 T cells recognizing tumor or chronic
pathogens have a division of labor: T cell factor (TCF)-1+ PD-1+ CD8 T cells function as memory-like resource
cells and TCF-1neg PD-1+ CD8 T cells have effector-like function. TCF-1+ PD-1+ CD8 T cells self-renew and
differentiate into effector-like and terminally differentiated/more exhausted TCF-1neg PD-1+ CD8 T cells. TCF-1+
memory-like cells have high expression CD28, and we have shown that during PD-1 targeted therapies CD28
costimulation is required for the reinvigoration of CD8 T cell responses. In addition, memory-like cells have high
expression of ICOS, and a gene expression program with similarities to follicular helper CD4 T cells. Our
preliminary data suggest that during established chronic lymphocytic choriomeningitis virus (LCMV) infection,
continuous CD28 signaling is required for differentiation and self-renewal of TCF-1+ memory-like PD-1+ CD8 T
cells. In contrast, ICOS signaling diminishes differentiation into effector-like cells. How memory-like cells choose
between self-renewal and differentiation, and how to modulate differentiation into effector-like cells are critical
questions. In addition to a unique set of costimulatory molecules, TCF-1+ memory-like cells also express a
distinct set of chemokine/cytokine receptors. Based on these data and the knowledge gap in the field, we propose
to define the role of costimulation in the maintenance and differentiation of PD-1+ CD8 T cells (Aim 1) and
uncover the impact of cellular interactions (Aim 2). In Aim 1, we will determine how CD28 and ICOS
costimulation affect TCF-1+ memory-like PD-1+ CD8 T cells and identify transcriptional regulators of T cell fate.
In Aim 2, we will use an unbiased approach to identify cellular interactions of TCF-1+ memory-like PD-1+ CD8 T
cells in vivo and probe the biological consequences of these interactions for T cell fate decisions. XCL-1, a
chemoattractant for XCR1+ dendritic cells (DC1) is highly expressed by TCF-1+ memory-like cells and modulated
by CD28 signaling. We will address the role of DC1 antigen presentation and XCL-1 production on localization,
differentiation and self-renewal of TCF-1+ memory-like PD-1+ CD8 T cells. Understanding the determinants of
self-renewal and differentiation of T cells chronically exposed to antigens would have broad implications for
immunotherapies in many pathologies (chronic infections, cancer, autoimmunity, transplantation and allergy).

## Key facts

- **NIH application ID:** 10843970
- **Project number:** 5R01AI153363-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Alice Oliffson Kamphorst
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $652,855
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843970

## Citation

> US National Institutes of Health, RePORTER application 10843970, Determinants of differentiation and maintenance of PD-1+ CD8 T cells (5R01AI153363-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10843970. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*