Project Summary
This R03 proposal is to follow-up on recent findings from my SERCA K01 award, which focuses on
elucidating the role of the type 1 diabetes (T1D) PTPN2 risk allele in loss of B cell anergy. Previously B cells
bearing antigen receptors with high affinity for insulin were found only in the anergic B cell compartment of
healthy individuals. Importantly, these cells leave this compartment in a proportion of first-degree relatives
(FDRs), and in all autoantibody positive pre-diabetics and recent onset T1D individuals. Departure of these
autoreactive anergic B cells in FDRs was shown to be associated with the high risk non-HLA allele, PTPN2
(rs1893217). PTPN2 has been previously shown to be a negative regulator of T cell signaling, but has not been
studied in B cells. Recently we demonstrated that mice that lack Ptpn2 specifically in their B cells
(Mb1Cre.Ptpn2fl/fl.C57BL/6) have a decrease in anergic B cells, similar to our findings in humans, an increase in
autoimmune associated B cells (ABCs), increase in production of autoreactive antibodies, and a hyperresponsive
phenotype. Despite these findings, these mice did not develop overt autoimmunity, likely driven by the fact these
mice are on the autoimmune resistant genetic background, C57BL/6. Hence, in this study we aim to determine
the effect of B cell specific deletion of Ptpn2 in the NOD mouse, which develops spontaneous diabetes by about
20 weeks of age. Specifically, we aim to study whether B cell deletion of Ptpn2 increases the rate and penetrance
of diabetes incidence, the effect on frequency and activation status of insulin-reactive and non-reactive B cells,
as well as its effect on B cell antigen presentation to T cells and the differentiation of pathogenic T cells. The
potential impact of these studies will lie in understanding how risk alleles conspire to undermine maintenance of
immune tolerance to autoantigens in T1D.