The selection of specific auto reactive T cell populations in diabetes and the effects of Nfkbid on the selection of specific T cell populations.

Isabel Stewart

Document Type

Article

Publication Date

Summer 2017

JAX Location

In: Student Reports, Summer 2017, Jackson Laboratory

Abstract

Type 1 diabetes (T1 D) is a debilitating autoimmune disease where autoreactive T-cells destroy insulin-producing r,3-cells. Both projects were centered around the development and selection of various T-cell populations. Project 1 was focused on the positive selection of both A14- and NYS.3-like Tcells in the absence of their cognate MHC-peptide combination. The purpose of this study is to better understand the genetics that result in the development of self-reactive CDS+ T-cells, looking specifically at the common Major Histocompatibility Complex (MHC; HLA in humans) class I molecules H2-Kd and H2-Db. These variants of MHC class I are associated with the development of two specific auto reactive T cell populations; NYS.3-like and Al4-like T-cells respectively. In order to observe the contribution of each variant to the development of these two autoreactive populations, we analyzed data taken from the Thymus (THY), Spleen (SPL), Pancreatic Lymph Nodes (PLN) and the Islets using tetramer analysis with MimA2, and NRPV7. The results suggest that these specific autoreactive T cells don't require their specific MHC-peptide combination for positive selection, however, it is required for their effector function. Project 2 focused on Nfkbid's role in negative selection of T-cell populations in the thymus. Tetramer analysis using PBS-CD1 d was used to look at natural killer Tcells (NKT), gamma delta T-cells (Gd) and T-follicular helper (Tfh) cells in THY, SPL and the PLN. The results suggest that Nfkbid does not have a significant impact on the development of Tfh or Gd T cells, but it does have a significant effect on the development of NKT cells and the maturation of CD4+ NKT cells in the THY. However, although there is an increase in CD4+ NKT cells in Nfkbid mice, it's insufficient to protect against diabetes, as the knockouts have a more rapid onset of diabetes.

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