The Role of Adenomatous Polyposis Coli in T cell biology: Development, Naïve T cell maintenance, and T cell Homeostatic Proliferation.

Abstract

T cell development begins with the migration of early progenitors from the bone marrow to the thymus. Once out of the thymus, naïve T cells are held in an inactive state until they encounter their cognate antigen/MHC complex to further differentiate into effector T cells. Many studies have shown that Wnt signaling is a crucial pathway that regulates many aspects of T cell biology from development to effector T cell polarization, however, little is known about the role of Wnt in naïve T cells. In this study, we show that Adenomatous polyposis coli (APC) is critical for the maintenance of naïve T cells. Wnt signaling has also been linked to cancers, though Wnt’s association with autoimmune disease is less known. Here, we show an association between ectopic dysregulation of Wnt causing a T-cell driven autoimmunity with a Crohn’s disease-like phenotype. Using an Apc conditional allele that has loxP sites inserted into introns 13 and 14 of the endogenous Apc gene under the control of a T cell specific cre-recombinase, CD4-Cre or Lck-cre, we can delineate the function of Apc in T cells. Flow cytometry, survival curves, and immunohistochemistry were used to study the T cell phenotype and autoimmune disease caused by ectopic activation of Wnt. Creation of bone marrow chimeras allowed us to investigate whether this T cell phenotype was cell-intrinsic and whether the observed autoimmunity was linked to homeostatic proliferation. Using an exon 3 deletion of cMyc, we studied the impact of transcriptional activation of cMyc. Though an Apc deficiency does not affect thymocyte development, we show that it does causes a massive cell-intrinsic loss of peripheral naïve T cells. We concluded that loss of Apc not only causes a loss of naïve T cells due to cMyc¬-induced apoptosis, but also results in highly activated T cells that drives the development of a Crohn’s disease-like phenotypes. Our study has further linked ectopic Wnt activation to autoimmunity through a T cell specific deletion of Apc, suggesting a direct role of Wnt in regulating T cell driven etiology of autoimmunity.