# Distinct contributions of CCR4 versus CCR7 to thymocyte localization and central tolerance

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $963,188

## Abstract

PROJECT ABSTRACT
Some COVID-19 patients fare well, experiencing asymptomatic or mild disease, while up to 20% of patients have
severe symptoms that can be fatal. Recent studies reveal elevated inflammatory cytokines and a reduced
number of T cells in patients with severe disease, indicating that variation in immune responses may underlie
differences in disease outcomes. However, features of protective versus pathologic immune responses to SARS-
CoV-2 are not well understood. Furthermore, children tend to experience milder symptoms, while elderly
individuals are more susceptible to severe disease, but it is not known if this is a function of age-associated
differences in immune responses. In Aim 1, we propose to carry out paired single-cell transcriptomics,
proteomics, and TCR repertoire sequencing of longitudinal blood samples from COVID-19 patients of different
ages and disease severities in order to comprehensively profile the trajectory of immune responses to SARS-
CoV-2 and identify candidate immune signatures that correlate with disease severity and age. Candidate
signatures will be tested and refined in a larger patient cohort. Current vaccine efforts are focused on eliciting
neutralizing antibodies against SARS-CoV-2. CD4+ T-cell responses are required to activate B cells to produce
neutralizing antibodies and to support differentiation of CD8+ T cells, which can promote viral clearance and
maintain immunologic memory. However, viral epitopes that activate protective T-cell responses remain
unknown. In Aim 2, we will activate T cells from the longitudinal patient samples used for single-cell profiling in
Aim 1 with “megapools” of overlapping peptides, spanning individual SARS-CoV-2 antigens. Activated T cells
will be subjected to single-cell multi-omics analysis, allowing us to identify TCR sequences of clones that respond
to each viral protein. Retrospective analysis of datasets from Aim 1 will enable us to follow the natural progression
of these individual clones to evaluate frequencies and differentiation over the course of disease. Using these
data, we will determine which viral antigens activate specific T-cell clones during effector and memory phases
that correlate with favorable outcomes at each age, informing vaccine design. The increased incidence in
autoimmune syndromes, such as the Kawasaki-like disease reported in pediatric patients, suggests that SARS-
CoV-2 may induce autoimmunity; conversely, patients with autoimmune syndromes may be more susceptible to
severe disease due to immune dysregulation. In Aim 3, we will explore both possibilities. Specifically, we will
retrospectively determine if autoimmunity predisposes patients to severe disease and if autoimmune patients
have more inflammatory T cell responses to SARS-CoV-2 antigens. We will also evaluate whether autoantigens
with high sequence similarity to SARS-CoV-2 peptides activate a higher frequency of T cells in COVID-19
patients versus uninfected controls, and we will ...

## Key facts

- **NIH application ID:** 10200461
- **Project number:** 3R01AI104870-07S1
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Lauren Ilyse Richie EHRLICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $963,188
- **Award type:** 3
- **Project period:** 2020-09-14 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200461

## Citation

> US National Institutes of Health, RePORTER application 10200461, Distinct contributions of CCR4 versus CCR7 to thymocyte localization and central tolerance (3R01AI104870-07S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10200461. Licensed CC0.

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