B Cell Receptor Affinity for Insulin Dictates Autoantigen Acquisition and B Cell Functionality in Autoimmune Diabetes.
B cells have been strongly implicated in the development of human type 1 diabetes and are required for disease in the NOD mouse model. These functions are dependent on B cell antigen receptor (BCR) specificity and expression of MHC, implicating linked autoantigen recognition and presentation to effector T cells. BCR-antigen affinity requirements for participation in disease are unclear. We hypothesized that BCR affinity for the autoantigen insulin differentially affects lymphocyte functionality, including tolerance modality and the ability to acquire and become activated in the diabetogenic environment. Using combined transgenic and retrogenic heavy and light chain to create multiple insulin-binding BCRs, we demonstrate that affinity for insulin is a critical determinant of the function of these autoreactive cells. We show that both BCR affinity for insulin and genetic background affect tolerance induction in immature B cells. We also find new evidence that may explain the enigmatic ability of B cells expressing 125 anti-insulin BCR to support development of TID in NOD mice despite a reported affinity beneath requirements for binding insulin at in vivo concentrations. We report that when expressed as an antigen receptor the affinity of 125 is much higher than determined by measurements of the soluble form. Finally, we show that in vivo acquisition of insulin requires both sufficient BCR affinity and permissive host/tissue environment. We propose that a confluence of BCR affinity, pancreas environment, and B cell tolerance-regulating genes in the NOD animal allows acquisition of insulin and autoimmunity.
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. thomas.packard@ucdenver.edu.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA. thomas.packard@ucdenver.edu.
Thomas A
TA
Packard
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. mia.smith@ucdenver.edu.|Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA. mia.smith@ucdenver.edu.
Mia J
MJ
Smith
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. frank@coloradogreenlab.com.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA. frank@coloradogreenlab.com.
Francis J
FJ
Conrad
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. johnson.sara@comcast.net.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA. johnson.sara@comcast.net.
Sara A
SA
Johnson
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Andrew.Getahun@ucdenver.edu.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA. Andrew.Getahun@ucdenver.edu.
Andrew
A
Getahun
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. robin.s.lindsay@ucdenver.edu.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA. robin.s.lindsay@ucdenver.edu.
Robin S
RS
Lindsay
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. rhinman99@gmail.com.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA. rhinman99@gmail.com.
Rochelle M
RM
Hinman
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. FriedmanR@NJHealth.org.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA. FriedmanR@NJHealth.org.
Rachel S
RS
Friedman
Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. james.w.thomas@vanderbilt.edu.
James W
JW
Thomas
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. john.cambier@ucdenver.edu.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA. john.cambier@ucdenver.edu.|Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA. john.cambier@ucdenver.edu.
John C
JC
Cambier
B cell antigen receptor; BCR; insulin; non-obese diabetic mouse (NOD); type 1 diabetes (T1D)