Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function–Associated Antigen-1 and Kindlin-3

Abstract

Kindlin-3 is an important integrin regulator that is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, a disorder characterized by defective neutrophil trafficking and platelet function, leading to recurrent bacterial infections and bleeding. Kindlin-3 is also known to regulate T cell adhesion in vitro and trafficking in vivo, but whether the integrin/kindlin interaction regulates T or B cell activation in vivo is unclear. In this study, we used TTT/AAA β2-integrin knock-in (KI) mice and TCR-transgenic (OT-II) KI mice, in which the integrin/kindlin connection is disrupted, to investigate the role of the integrin/kindlin interaction in T cell activation. We show that basal T cell activation status in these animals in vivo is normal, but they display reduced T cell activation by wild-type Ag-loaded dendritic cells in vitro. In addition, T cell activation in vivo is reduced. We also show that basal Ab levels are normal in TTT/AAA β2-integrin KI mice, but B cell numbers in lymph nodes and IgG and IgM production after immunization are reduced. In conclusion, we show that the integrin/kindlin interaction is required for trafficking of immune cells, as well as for T cell activation and B cell Ab responses in vivo. These results imply that the immunodeficiency found in leukocyte adhesion deficiency type III patients, in addition to being caused by defects in neutrophil function, may be due, in part, to defects in lymphocyte trafficking and activation.

The Integrin LFA-1 Controls T Follicular Helper Cell Generation and Maintenance

“…One member of the integrin family, leukocyte function-associated antigen (LFA)-1, is composed of the αL and β2 subunits and has been shown to be a potent intercellular adhesion and co-stimulatory molecule for T cell activation in vitro (Dubey et al, 1995; Dustin and Springer, 1989). These findings have been substantiated by in vivo studies in which deficiency in either subunit compromises T cell priming and is associated with decreased antigen-specific antibody production in humans and mice (Fischer et al, 1986; Kandula and Abraham, 2004; Morrison et al, 2015; Peters et al, 2012). Importantly, LFA-1 activity is not only regulated by its expression but also by its conformation on the cell surface.…”

The kindlin family: functions, signaling properties and implications for human disease

“…Hence, in experimental autoimmune encephalitis (EAE), a model for multiple sclerosis with a high expression of integrin ligand in the inflamed tissue, inhibition of kindlin-3 is probably not sufficient to block extravasation of autoreactive T cells and disease progression (Moretti et al, 2013). Kindlin-3 is also required for B-cell adhesion under flow (Willenbrock et al, 2013), trafficking into lymph nodes and immunoglobulin expression (Morrison et al, 2015). Furthermore, dendritic cells display enhanced granulocyte-macrophage colonystimulating factor (GM-CSF) receptor/Syk signaling associated with an accumulation of mature, migratory dendritic cells in lymphoid organs and an increased Th1 immune responses in vivo when the kindlin-3 interaction with β2 integrins is impaired .…”

Filamin A Is Required for Optimal T Cell Integrin-Mediated Force Transmission, Flow Adhesion, and T Cell Trafficking

“…CD4-Cre + (Ctrl) mice were used as controls for FlnA KO-CD4-Cre mice. For in vivo T cell activation studies, FlnA KO mice were crossed with TCR-OT-II-transgenic mice (4). FlnA and CD4-Cre mice were ordered from The Jackson Laboratory.…”

“…FlnA binds to the LFA-1 integrin (5, 8), and we show above that FlnA is necessary for the formation of strong LFA-1-ICAM-1 bonds under force and for integrin force transmission. Functional LFA-1 is important for T cell activation in vivo (4). Therefore, to investigate the role of the integrin regulator FlnA in T cell activation in vivo, FlnA KO mice were crossed with TCRtransgenic (OT-II) mice.…”

“…They are essential for T cell trafficking out from the bloodstream and into tissues in homeostasis and inflammation because they mediate the firm adhesion to ICAMs expressed on endothelial cells under shear force conditions (blood flow). The b 2 integrin LFA-1 (aLb 2 ) is also a component of the immunological synapse between a T cell and an APC, aiding in the stabilization of the contact, and it is required for optimal T cell activation in vitro and in vivo (3,4).…”