# A novel CD4+ T cell helper population in Lupus Nephritis

> **NIH NIH U19** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $254,250

## Abstract

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by breakdown of
tolerance to nucleic acids (NAs) and widespread inflammation. While nucleosomal DNA released
from apoptotic cells is considered an important initiator of the autoimmune response in SLE, we
and others have reported that live neutrophils might contribute to disease pathogenesis by
releasing protein-bound oxidized mitochondrial DNA (Ox mtDNA) that activate plasmacytoid
dendritic cells (pDCs) to produce Interferon (IFN). Our new data support that Ox MtDNA-activated
pDCs prime and polarize naive CD4+ T cells towards a distinctive phenotype characterized by a
Tr1-like cytokine profile (IFN, IL10), high expression of PD1 and the upregulation of a cytotoxic
program. These cells generate mtROS through reverse electron transfer (RET) fueled by the citric
acid metabolite succinate. Importantly, they help B cells through a unique and novel
cytokine/metabolite combination: IL10 and succinate. Moreover, extrafollicular (CXCR5neg) CD4+
T helper cells with similar characteristics (Th10) are expanded in SLE patient’s blood and found
in the tubulointerstitial areas of proliferative lupus nephritis (PLN) patients where they often
associate with B cells. Indeed, we hypothesize that these CD4+ T cells contribute to extrafollicular
autoantibody production and kidney damage and that they represent a valuable biomarker of PLN.
Here, we propose: 1) to characterize the blood CD4+ T helper cell compartment of SLE patients
and to determine, in longitudinal studies, the value of Th10 cells as a biomarker of Lupus nephritis;
2) to identify the mechanisms and cellular targets involved in Th10 cell-B cell help, determine
whether unique B cell subsets respond to the cytokine/metabolite combination and whether
autoreactive B cells are preferentially selected under these conditions; 3) to determine whether
the interaction between succinate-producing Th10 cells and myeloid cells contributes to SLE
pathogenesis. Overall, we expect that these studies will provide valuable insights into the role of
this new T cell population in SLE. Furthermore, this work may identify useful biomarkers to stratify
LN and new ways to interfere with Th10 cell generation/activation and ultimately improve the
outlook of our patients.

## Key facts

- **NIH application ID:** 10159209
- **Project number:** 5U19AI144301-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Maria Virginia Pascual
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $254,250
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159209

## Citation

> US National Institutes of Health, RePORTER application 10159209, A novel CD4+ T cell helper population in Lupus Nephritis (5U19AI144301-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10159209. Licensed CC0.

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