# Project 1 - Dioxin-like Compounds Suppress IgM Responses by Targeting CD5+ (Innate-like) B cells, which can Serve as a Biomarker of Susceptibility to Environmental AHR Ligands

> **NIH NIH P42** · MICHIGAN STATE UNIVERSITY · 2022 · $253,536

## Abstract

PROJECT SUMMARY/ABSTRACT: Suppression of humoral immunity by environmental contaminants that
are prototypical aryl hydrocarbon receptor (AHR) ligands (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD))
have been demonstrated to suppress humoral immunity in laboratory animals and suggested by
epidemiological evidence. The overall goal of this research is to define the molecular mechanism(s)
responsible for AHR agonist-mediated suppression of antibody production by human primary B cells. Prior
studies comparing activated mouse, rat and human primary B cells, RNAseq showed a small number of
differentially expressed genes by TCDD. One gene that was only differentially regulated in human B cells
compared to mouse and rat was the lymphocyte specific protein tyrosine kinase (LCK). While LCK is
expressed by T cells, subpopulations of B cells also express LCK, specifically CD5+ B cells. We have shown
that decreased IgM secretion by TCDD is due, in part, to selective effects on CD5+ B cells, termed innate-like B
(ILB) cells. Although CD5+ ILBs constitute approximately 10-25% of circulating B cells and are the source for
the majority of circulating IgM in the absence of an immune response. Further, CD5+ ILBs are the primary B
cell type mediating humoral immunity early and late in life when the adaptive immune system is still developing
or during late life stages when adaptive immunity is in decline. Protein analysis also showed induction by
TCDD of LCK, the inhibitory receptor PD-1 and its ligand, PD-L2 on CD5+ ILBs. Induction of PD-1 and PD-L2
are especially important as they provide a mechanism for the suppression of the IgM response by AHR
activation in CD5+ ILBs. LCK can phosphorylate the inhibitory region of the PD-1 receptor, facilitating immune
suppression by PD-1. Inhibition of LCK activity protected CD5+ B cells from IgM suppression by TCDD,
demonstrating LCK is critically involved. Therefore, we will test the hypothesis: AHR-mediated suppression of
IgM occurs through induction of the inhibitory receptor PD-1 and LCK, a kinase known to initiate PD-1-
mediated immune regulation, preferentially on human primary CD5+ (innate-like) B cells. Specific Aim (SA) 1
will characterize human CD5+ (innate-like) B cells as a highly sensitive population susceptible to suppression
by AHR ligands. SA2 is to identify the role of induced checkpoint inhibitor, PD-1, and tyrosine kinase, LCK, in
TCDD-mediated suppression of IgM production by CD5+ B cells. Completion of the above aims has a strong
potential to: (a) define B cell population(s) highly sensitive to impairment by AHR ligands critical for immunity
against common pathogens; (b) identify a novel mechanism of immunotoxicity involving upregulation of the
inhibitory receptor, PD-1; (c) characterize the role of LCK in IgM suppression by AHR activation using IFNγ as
a molecular probe; (d) utilize percent circulating CD5+ B cells as biomarker of sensitive populations to
suppression of IgM by AHR ligands and (e) resul...

## Key facts

- **NIH application ID:** 10353531
- **Project number:** 2P42ES004911-27A1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Norbert E Kaminski
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $253,536
- **Award type:** 2
- **Project period:** 1997-04-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353531

## Citation

> US National Institutes of Health, RePORTER application 10353531, Project 1 - Dioxin-like Compounds Suppress IgM Responses by Targeting CD5+ (Innate-like) B cells, which can Serve as a Biomarker of Susceptibility to Environmental AHR Ligands (2P42ES004911-27A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10353531. Licensed CC0.

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