# Investigating the Repertoires and Functions of T Cells that Help Autoreactive B Cells in Lupus

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $382,775

## Abstract

Lupus is a devastating disease predominantly affecting young women. Lupus autoimmunity is
prototypical of many different autoimmune diseases, which together affects 3-5% of the popula-
tion. T cells, whose activation depends on both B cells and innate immune sensing, are pivotal
in promoting disease. Despite that T cells are critical in driving virtually all aspects of systemic
autoimmune disease, their identity, specificity, function and fate remain very poorly defined. Au-
toreactive T cells provide help to autoreactive B cells and also cause tissue damage by target
organ infiltration. While we have a deep understanding of the specificity, regulation and fate of
autoreactive B cells, the same cannot be said for autoreactive T cells. In particular, we would
like to elucidate how self-reactive T cells are regulated by self-tolerance mechanisms and how,
upon activation, they contribute to various aspects of autoimmunity.
With the current proposal we hope to make significant inroads into this important yet understud-
ied area. We will first use a novel strategy to isolate new clones of autoreactive T cells that rec-
ognize nuclear components (“ANA T cells”) from both normal and autoimmune prone genetic
backgrounds (Aim 1A); this will provide insights into the repertoire of autoimmune B-helper T
cell repertoire. We will then clone the TCRs of selected T cells into retroviral expression vectors
to make “retrogenic” (Rg) mice. We will then determine (Aim 1B) how these autoreactive cells
develop, are subject to a variety of tolerance mechanisms, and are potentially spontaneously
activated. This will be studied according to both the origin of the T cell as well as the context in
which the T cell is expressed (normal or autoimmune background). Finally in Aim 1(C), we will
convert selected TCRs into full-fledged TCR transgenic (Tg) mice, which will be required for
more robust and detailed mechanistic studies. In Aim 2 we will then use these Tg mice T cells to
study mechanisms of activation, T-B interaction and Toll-like receptor (TLR) dependence. This
will be done by a series of mixed bone marrow chimeras that will allow us to interrogate the fate
and function of ANA T cells in a more natural milieu in which the T cells will develop and operate
in the context of polyclonal autoimmunity driven by the other cells in the chimera that will vary in
expression of cognate BCRs as well as TLR signaling capability.
At the conclusion of these studies we will not only have a truly unique set of new tools in the
form of clones, Rg mice and Tg mice on normal and autoimmune backgrounds, but we will have
very significantly advanced the field in terms of understanding how ANA T cells are activated
and regulated, how they promote disease, and how they interact with innate immune signals.

## Key facts

- **NIH application ID:** 9825508
- **Project number:** 5R01AI137132-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** MARK J SHLOMCHIK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,775
- **Award type:** 5
- **Project period:** 2017-12-22 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9825508

## Citation

> US National Institutes of Health, RePORTER application 9825508, Investigating the Repertoires and Functions of T Cells that Help Autoreactive B Cells in Lupus (5R01AI137132-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9825508. Licensed CC0.

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