Antigen Recognition in the Islets Changes with Progression of Autoimmune Islet Infiltration

Abstract

In type 1 diabetes, the pancreatic islets are an important site for therapeutic intervention since immune infiltration of the islets is well established at diagnosis. Therefore, understanding the events that underlie the continued progression of the autoimmune response and islet destruction is critical. Islet infiltration and destruction is an asynchronous process, making it important to analyze the disease process on a single islet basis. To understand how T cell stimulation evolves through the process of islet infiltration we analyzed the dynamics of T cell movement and interactions within individual islets of spontaneously autoimmune non-obese diabetic (NOD) mice. Using both intra-vital and explanted 2-photon islet imaging, we defined a correlation between increased islet infiltration and increased T cell motility. Early T cell arrest was antigen dependent and due, at least in part, to antigen recognition through sustained interactions with CD11c+ antigen presenting cells (APCs). As islet infiltration progressed, T cell motility became antigen-independent, with a loss of T cell arrest and sustained interactions with CD11c+ APCs. These studies suggest that the autoimmune T cell response in the islets may be temporarily dampened during the course of islet infiltration and disease progression.

T cell migration, search strategies and mechanisms

“…In this context, CTLs must locate APCs to maintain cytotoxicity 78, 79 . Similarly, CTLs interact with DCs in the pancreas during Type 1 Diabetes 80 , necessary for optimal effector function and disease progression 81 . CD4 T cells similarly reencounter antigen in tissues.…”

Longitudinal three-dimensional visualisation of autoimmune diabetes by functional optical coherence imaging

“…While the medical potential of these modalities is indisputable, they are limited by a restricted set of reagents targeting specific tissues and by a relatively low spatial resolution [4,7,8]. Optical microscopy on the other hand is mainly limited to preclinical studies because of a reduced penetration depth [9][10][11][12]. Optical projection tomography (OPT) has been used to image the adult mouse pancreas and retrieve the three-dimensional (3D) and undistorted structure of the tissue [13].…”

Immunotherapies and immune biomarkers in Type 1 diabetes: A partnership for success

“…A number of immune biomarkers have been pursued in the NOD, including Treg to effector ratios, CD4-dependent cytokine responses, frequency of disease-specific CD8 and CD4 T-cells, circulating cytokines, antigen presenting cell activation status and frequency, and autoantibody titers. Often, these are measured using splenic tissue, lymph nodes, or pancreatic tissue rather than blood or serum [50][51][52]. Immune biomarkers requiring any tissue other than blood will be challenging to translate to human populations.…”