# Mechanisms maintaining the self-awareness of peripheral T cells

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $231,750

## Abstract

Summary: Mechanisms maintaining the self-awareness of peripheral T cells
The ability of T cells in our peripheral immune system to robustly respond when stimulated by
their antigen is highly desirable in the context of repelling attacks by dangerous pathogens. In
contrast, strong T cell responses to self-antigens would be pathogenic, leading to autoimmune
disease. Therefore, as a central tenet of the clonal selection theory, the immune system is
expected to eliminate strongly autoreactive T cells during development in the thymus and dampen
the remaining self-reactivity by peripheral mechanisms. In this context, it is surprising that all T
cells undergo positive selection on self-peptides in the thymus – ensuring that they are all at least
nominally self-reactive. After positive selection a series of TCR-proximal tuning mechanisms,
including the upregulation of a cell-surface glycoprotein CD5, ensures that this self-reactivity is
not pathogenic. In recent years it is increasingly clear that despite such tuning, peripheral T cells
not only continue to be aware of their self-ligands but also use this self-awareness to promote
responses to pathogens. The mechanisms of these linked processes are not fully understood.
Based on our preliminary studies, we propose that biochemical signals downstream of CD5 itself
help to promote the preferential activation and survival of better self-aware T cells in the peripheral
Immune system. Here, we propose to use CD5-conditional-knockout mice and infectious
challenges to test this hypothesis. The significance of these studies is that it is expected to provide
a more comprehensive model for how self-recognition synergizes with pathogen-specific
responses in the T cell compartment. The insights gained from these studies can lead to future
translational approaches improving the design of vaccines as well as informing the selection and
design of T cell transfer therapies.

## Key facts

- **NIH application ID:** 10242775
- **Project number:** 5R21AI149076-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Nevil John Singh
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $231,750
- **Award type:** 5
- **Project period:** 2020-08-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242775

## Citation

> US National Institutes of Health, RePORTER application 10242775, Mechanisms maintaining the self-awareness of peripheral T cells (5R21AI149076-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10242775. Licensed CC0.

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