Tu133 - FoxP3 Lo T Cells Are Induced in Autoimmune Inflammation and Likely Represent Regulatory T Cells with Reduced Suppressive Capacity

Abstract Text:

Background:
Human FoxP3 expressing T cells can be divided into FoxP3-Lo and FoxP3-Hi subsets. The
function and role of FoxP3-Lo T cells remains unclear. We examined FoxP3-Lo T cells across
patients with systemic sclerosis (SSc), IgG4-related disease (IgG4-RD), and sarcoidosis.

Methods:
We used intracellular spectral flow cytometry to examine circulating Treg subsets. We
used bulk RNA sequencing of purified T cell populations to define the transcriptional
differences between subsets. Purified Treg subsets were used for in vitro activation and
suppression studies.

Results:
In SSc and IgG4-RD, two progressive autoimmune diseases, FoxP3-Lo T cells, which
have previously been shown to have a non-suppressive phenotype, were preferentially
expanded and correlate with disease severity, whereas FoxP3-Hi T cells were not. In
contrast, patients with clinically stable sarcoidosis, showed expansion of both FoxP3-Lo
and FoxP3-Hi compartments. Transcriptionally, CD127-Lo CD25-Lo T cells closely resemble
their CD127-Lo CD25-Hi counterparts but with reduced expression of IKZF2, IL2R, FOXP3,
CTLA4, and activation markers including CD30, CD70, and HLA-DR. Functionally,
CD127-Lo CD25-Lo T cells can be further activated with prominent upregulation of CTLA4
and show an intermediately suppressive capacity.

Conclusion:
We show that FoxP3+ T cells expressing low levels of FoxP3 are bona fide regulatory T
cells but display reduced suppressive functionality. These cells are expanded in settings
of chronic inflammation. The correlation of FoxP3-Lo T cells with disease severity in SSc
and IgG4-RD suggests that these cells either have a pathogenic role or reflect a distorted
Treg phenotype that is permissive to T cell driven inflammation.