Role of Programmed Cell Death Protein-1 and Lymphocyte Specific Protein Tyrosine Kinase in the Aryl Hydrocarbon Receptor- Mediated Impairment of the IgM Response in Human CD5+ Innate-Like B Cells

Abstract

Innate-like B cells (ILBs) are a heterogeneous population B cells which participate in innate and adaptive immune responses. This diverse subset of B cells is characterized by the expression of CD5 and has been shown to secrete high levels of immunoglobulin M (IgM) in the absence of infection or vaccination. Further, CD5+ ILBs have been shown to express high basal levels of lymphocyte specific protein tyrosine kinase (LCK) and programmed cell death protein-1 (PD-1), which are particularly sensitive to stimulation by interferon gamma (IFNγ). Previous studies have demonstrated that activation of the aryl hydrocarbon receptor (AHR), a cytosolic ligand-activated transcription factor, results in suppressed IgM responses and is dependent on LCK. A recent study showed that CD5+ ILBs are particularly sensitive to AHR activation as evidenced by a significant suppression of the IgM response compared to CD5- B cells, which were refractory. Therefore, the objective of this study was to further investigate the role of LCK and PD-1 signaling in AHR-mediated suppression of CD5+ ILBs. In addition, studies were conducted to establish whether IFNγ alters the levels of LCK and PD-1 in CD5+ ILBs. We found that AHR activation led to a significant upregulation of total LCK and PD-1 proteins in CD5+ ILBs, which correlated with suppression of IgM. Interestingly, treatment with recombinant IFNγ reduced LCK protein levels and reversed AHR-mediated IgM suppression in CD5+ ILBs in a similar manner as LCK inhibitors. Collectively, these results support a critical role for LCK and PD-1 in AHR-mediated suppression of the IgM response in human CD5+ ILBs.

B-1 cells in immunotoxicology: Mechanisms underlying their response to chemicals and particles

“…Recent studies on human samples presented similar results on the importance of AHR in B-1-like cells (Blevins et al, 2021;Zhou et al, 2022). Human CD5 + B cells resemble mouse B-1 cells, with innate-like cells releasing the vast majority of the natural IgM in an age-related manner.…”

“…These microenvironments contain a low number and frequency of B-1 cells, whose activation is notably regulated via CXCR4+ Tregs ( Stoermann et al, 2007 ; Elias et al, 2022 ). Similar to T cells, B-1 cells express the inhibitory surface markers CD5 ( Berland and Wortisoorelbeke, 2002 ; Smith and Baumgarth, 2019 ), PD-1 ( Blevins et al, 2021 ; Zhou et al, 2022 ), and CTLA-4 ( Yang et al, 2021 ) to regulate their activation.…”

“…It was also found that TCDD-mediated AHR activation on CD5 + B cells significantly increased surface PD-1 and inhibited IgM production. Additionally, lymphocyte-specific protein tyrosine kinase (LCK) is upregulated via AHR activation in these cells and further suppresses IgM release by acting on the same pathway ( Blevins et al, 2021 ; Zhou et al, 2022 ). Interestingly, the increase in LCK has been implicated as a biomarker for the progression of chronic lymphoid leukemia.…”