Krüppel-like factor 2 controls IgA plasma cell compartmentalization and IgA responses

Abstract

Krüppel-like factor 2 (KLF2) is a potent regulator of lymphocyte differentiation, activation and migration. However, its functional role in adaptive and humoral immunity remains elusive. Therefore, by using mice with a B cell-specific deletion of KLF2, we investigated plasma cell differentiation and antibody responses. We revealed that the deletion of KLF2 resulted in perturbed IgA plasma cell compartmentalization, characterized by the absence of IgA plasma cells in the bone marrow, their reductions in the spleen, the blood and the lamina propria of the colon and the small intestine, concomitant with their accumulation and retention in mesenteric lymph nodes and Peyer’s patches. Most intriguingly, secretory IgA in the intestinal lumen was almost absent, dimeric serum IgA was drastically reduced and antigen-specific IgA responses to soluble Salmonella flagellin were blunted in KLF2-deficient mice. Perturbance of IgA plasma cell localization was caused by deregulation of CCR9, Integrin chains αM, α4, β7, and sphingosine-1-phosphate receptors. Hence, KLF2 not only orchestrates the localization of IgA plasma cells by fine-tuning chemokine receptors and adhesion molecules but also controls IgA responses to Salmonella flagellin.

Single-cell transcriptomics reveals colonic immune perturbations during amyloid-β driven Alzheimer’s disease in mice

“…2A, Fig. S3B), transcription factors that regulate B cell migratory programs [55] and IgA responses [56]. Under pathological conditions, gut-specific ASCs emigrate to sites of peripheral inflammation [57,58], especially the CNS [27,59].…”

Antigen receptor signaling and cell death resistance controls intestinal humoral response zonation

“…Thus, additional step(s) that control functional generation of intestinal humoral immunity must take place in PPs during the response to intestinal antigen. While the homing ability could be imprinted during LZ selection in the GC, it could also be imprinted on plasmablasts and even fully differentiated PCs, which can maintain BCR surface receptor expression 75,76 , suggesting that BCR signaling could shape PC homing outside of the GC reaction.…”

The intestine: A highly dynamic microenvironment for IgA plasma cells

“…We have identified the transcription factor Krüppel-like factor 2 (KLF2) as a key regulator of integrin α4β7 and CCR9 expression and consequently as an essential regulator of IgA plasmablast homing to the intestinal LP. B cell-specific deletion of KLF2 resulted in reduced integrin β7 and CCR9 expression and subsequently in a severe reduction of IgA plasmablasts/plasma cells in the LP concomitant with reduced IgA in the serum and in the gut lumen ( 77 , 78 ). Besides CCR9 and integrin β7, KLF2 also activates L-Selectin (CD62L) expression in B cells and IgA plasma cells ( 77 – 79 ).…”

“…B cell-specific deletion of KLF2 resulted in reduced integrin β7 and CCR9 expression and subsequently in a severe reduction of IgA plasmablasts/plasma cells in the LP concomitant with reduced IgA in the serum and in the gut lumen ( 77 , 78 ). Besides CCR9 and integrin β7, KLF2 also activates L-Selectin (CD62L) expression in B cells and IgA plasma cells ( 77 – 79 ). Of note, KLF2 directly binds to the promoter of the integrin β7 gene and activates its expression ( 80 ).…”

“…4) How do signals mediated by the IgA surface BCR on plasma cells affect their localization, survival, and function? IgA plasmablasts and, more importantly, mature IgA plasma cells still express IgA-BCRs on their cell surface ( 77 , 214 – 216 ). However, the biological function of their IgA-BCR expression remains elusive.…”