# The Role of Checkpoint inhibitors in CIA

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2020 · $45,520

## Abstract

Abstract
Immune related adverse events linked to severe inflammatory arthritis have been identified in 10-43% of patients
receiving immune checkpoint inhibitors, αCTLA4, αPD-1 or αPD-L1, indicating the importance of immune
inhibitory pathways in maintaining homeostasis in the joints. We obtained human synovial fluid and found a high
frequency of PD-L1 expression by synovial macrophages. We propose to examine the role of PD-L1 expression
in synovial macrophages and T cells during murine collagen induced arthritis (CIA). We found that immune
checkpoint inhibitor, PD-L1, is primarily expressed in the joint compared to other immune checkpoints.
Additionally, we found synovial macrophages and CD3+ T cells are the main PD-L1 expressing cells in the joint,
and PD-L1 expression is increased during CIA. We extensively profiled the synovial macrophages and found
three populations of PD-L1 expressing cells: F4/80intCD115+CCR2-MHCII-CD73-Tim4-PD-L1hi (CD115+
macrophages), F4/80hiCD115-CCR2intMHCIIhiCD73intTim4intPD-L1int (MHCII+ macrophages), and F4/80intCD115-
CCR2lowMHCII-CD73loTim4intPD-L1int (F4/80+ macrophages). We have also found that PD-L1 has the highest
frequency of expression in CD4+ and CD8+ T cells. Furthermore, we identified a novel subset of joint tissue
resident memory T cells in the naïve joint that are phenotypically CD8+CD69+ and CD8+CD69+CD103+. We
hypothesize that the expression of PD-L1 by macrophages and/or T cells are essential for synovial
homeostasis and regulation of joint inflammation. In Aim 1, we will examine the importance of PD-L1
expression by synovial macrophages through the selective deletion of PD-L1 using the cre/flox system. We will
generate two macrophages specific PD-L1 KO mice, LyzcrePD-L1fl/fl and CD115crePD-L1fl/fl. We will induce CIA in
LyzcrePD-L1fl/fl, CD115crePD-L1fl/fl, Lyzcre and CD115cre mice and harvest the joint to determine the protective role
of synovial macrophage PD-L1 expression in CIA (Subaim 1.1). We will also perform parabiosis experiments by
surgically joining CD45.1 C57BL6 and CD45.2 CD115crePD-L1fl/fl to determine if PD-L1+ synovial macrophages
are resident or bone marrow derived during CIA (Subaim 1.2). We have found that PD-L1 is highly expressed
in synovial T cells. In Aim 2, we will examine the protective function of synovial T cells following CIA. We will use
LckcreP D-L1fl/fl mice, which lack PD-L1 expression in CD3+ T cells to examine the effects of PD-L1 specific
deletion in T cells during CIA (Subaim 2.1). To test if tissue resident memory T cells play a protective role during
CIA, we will utilize a tissue resident chimera mouse model to selectively delete peripheral T cells in LckcrePD-
L1fl/fl mice. Donor T cells from LckcrePD-L1fl/fl or Lckcre mice will replace peripheral T cell populations to confirm
the protective function of tissue resident memory T cells in the joint (Subaim 2.2). Our project has high
translational potential since joint specific PD-L1 expression could be modulated ...

## Key facts

- **NIH application ID:** 9992355
- **Project number:** 1F31AR077406-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Megan Kay Wood
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992355

## Citation

> US National Institutes of Health, RePORTER application 9992355, The Role of Checkpoint inhibitors in CIA (1F31AR077406-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9992355. Licensed CC0.

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