Lymphocyte-specific protein tyrosine kinase (LCK) is involved in the aryl hydrocarbon receptor (AHR)-mediated impairment of Immunoglobulin secretion in human primary B cells

Abstract

Abstract AHR activation by the high affinity ligand, TCDD, is widely established to suppress the immunoglobulin M (IgM) response in virtually every animal species tested, and extensively investigated in various mouse models. In mice, activation of AHR is known to impair B cell to plasma cell differentiation and IgM synthesis. In contrast to mouse B cells, activation of AHR in human primary B cells impairs immunoglobulin secretion in the absence of suppressing IgM synthesis. In recent studies, we have identified the putative involvement of LCK in impaired immunoglobulin secretion by human B cells. LCK is a well-characterized tyrosine kinase that phosphorylates known critical signaling proteins involved in vesicular secretion by T cells. Specifically, phosphorylation of tyrosine residue 505 inhibits the activity of LCK. By contrast, little is known concerning the role of LCK in human primary B cells. For the first time, our studies show that activation of the AHR by TCDD upregulates LCK protein expression, which then leads to an impairment of IgM secretion. Treatment with a LCK specific inhibitor restores IgM secretion by human primary B cells. Additionally, the presence of AHR antagonist reverses the AHR-mediated increase of LCK and the impairment of IgM secretion. We also observe a significant increase in phosphorylation of Tyr-505 LCK with TCDD treatment, indicating that AHR activation increases the level of inhibitory LCK. Taken together, our studies revealed a novel and species-dependent mechanism involving the AHR-mediated impairment of IgM secretion and an increase in total as well as inhibitory LCK in human but not mouse primary B cells.