# Altered T Cell Responses in Myalgic Enchephalomeylitis/Chronic Fatigue Syndrome (ME/CFS)

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $488,934

## Abstract

Project Summary/Abstract
Myalgic enchephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder affecting numerous organ
systems and biological processes. Published data seems to suggest that ME/CFS may be preceded by infection,
and the chronic manifestation of illness may represent an altered host response to infection, or an inability to
resolve inflammation. Previous studies focused on perturbation in cytokines and metabolism have also shown
that CD8 T responses are decreased in ME/CFS. In preliminary studies we examined the frequency, functional
and phenotypic status of CD8 T cells to determine whether they were altered in chronic ME/CFS donors as
compared to healthy donors. We observed an increased CD4:CD8 ratio, altered expression of
exhaustion/activation markers like CTLA4 and 2B4 on CD8 T cells, and decreased production of IFN, TNF
and CD107a/b upregulation following PMA stimulation, all suggesting CD8 T cell exhaustion. This was
associated with a, perhaps compensatory increased frequency of activated CD4+CD8+ T cells in the ME/CFS
donors as compared to healthy controls. Notably, a subset of the CD8 and the CD4+CD8+ T cell populations
were spontaneously producing atypical cytokines, subdividing ME/CFS donors into two subsets: type 1 had an
increased frequency of FoxP3+helios+ Treg-like cells producing IL9 (female donors); type 2 had FoxP3+helios-
cells producing IL17 (male donors). When we examined the T-cell receptor (TCR) repertoire of the CD4+CD8+ T
cell population we found evidence of antigen driven clonal expansions to an unknown antigen at this time,
whether it will be a viral or auto-antigen. We hypothesize that the common theme in ME/CFS is an aberrant
response to an immunological trigger like infection, which results in a permanently dysregulated immune system
as a result of CD8 T cell exhaustion. These studies will identify potential biomarkers and mechanisms driving
the immunopathogenesis of ME/CFS leading to future therapies. We will explore this hypothesis in the following
Aims. Aim 1 we will examine altered CD8 and CD4+CD8+ T-cell responses in ME/CFS: 1) we will determine if
the level of CD8 T cell exhaustion varies with ME/CFS type 1 (female) and Type 2 (male) response and with the
severity of ME/CFS symptoms using a larger ME/CFS cohort; 2) we will examine EBV antigen-specific responses
in ME/CFS donors to determine if a common persistent virus response is altered by the immunosuppressive
state of CD8 T cell exhaustion and further contributing to the disease state of ME/CFS; 3) microarray analyses
will be done on sorted activated T cell subsets to assist in understanding the alterations in the functionality of the
exhausted and activated CD8 and CD4+CD8+ T cell subsets in ME/CFS donors. In Aim 2 we will examine TCR
repertoire of CD8 and CD4+CD8+ T-cell subsets for evidence of antigen driven clonal expansion. Defining the
characteristics of the activated clonally expanded CD8 and CD4+CD8+ T cells would be a ma...

## Key facts

- **NIH application ID:** 10368149
- **Project number:** 5R01AI159314-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Liisa Kaarina Selin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $488,934
- **Award type:** 5
- **Project period:** 2021-03-08 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368149

## Citation

> US National Institutes of Health, RePORTER application 10368149, Altered T Cell Responses in Myalgic Enchephalomeylitis/Chronic Fatigue Syndrome (ME/CFS) (5R01AI159314-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10368149. Licensed CC0.

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