Kindlin‐3 maintains marginal zone B cells but confines follicular B cell activation and differentiation.

Integrin‐mediated interactions between hematopoietic cells and their microenvironment are important for the development and function of immune cells. Here, the role of the integrin adaptor Kindlin‐3 in B cell homeostasis is studied. Comparing the individual steps of B cell development in B cell‐specific Kindlin‐3 or alpha4 integrin knockout mice, we found in both conditions a phenotype of reduced late immature, mature, and recirculating B cells in the bone marrow. In the spleen, constitutive B cell‐specific Kindlin‐3 knockout caused a loss of marginal zone B cells and an unexpected expansion of follicular B cells. Alpha4 integrin deficiency did not induce this phenotype. In Kindlin‐3 knockout B cells VLA‐4 as well as LFA‐1‐mediated adhesion was abrogated, and short‐term homing of these cells in vivo was redirected to the spleen. Upon inducible Kindlin‐3 knockout, marginal zone B cells were lost due to defective retention within 2 weeks, while follicular B cell numbers were unaltered. Kindlin‐3 deficient follicular B cells displayed higher IgD, CD40, CD44, CXCR5, and EBI2 levels, and elevated PI3K signaling upon CXCR5 stimulation. They also showed transcriptional signatures of spontaneous follicular B cell activation. This activation manifested in scattered germinal centers in situ, early plasmablasts differentiation, and signs of IgG class switch. [ABSTRACT FROM AUTHOR]