News & Research

    University of Colorado, Denver, Denver, Colorado

Expression and Function of CD40 on Autoreactive T Cells in T1D

General Research Subject: Type 1 Diabetes

Focus: Immunology

Type of Grant: Basic Science

Project Start Date: January 1, 2010

Project End Date: December 31, 2012

Research Description

The objective of this proposal is to determine how the signaling molecule CD40 contributes to T cell pathogenicity in the NOD mouse model of autoimmune diabetes and to determine whether CD40 can also act as an amplifier of the autoimmune response in human type 1 diabetes. Autoreactive T cells in T1D express CD40 and the Haskins' lab has shown that blocking CD40 on T cells alters their ability to cause diabetes, suggesting that signaling through CD40 might be necessary for T cell pathogenicity. CD40 can also be found at high levels on human T cells reactive with islet antigens, but its role in disease has not been determined. The underlying hypothesis of this proposal is that by preventing signaling through CD40 on autoreactive T cells, immune regulation may be restored. 

The aims of this project are to (1) determine how inhibition of CD40 signaling on autoreactive CD4 T cells affects T cell activation, function and disease transfer capacities; (2) investigate how signaling through CD40 on diabetogenic T cells inhibits function of the negative regulatory molecule, CTLA-4; and (3) determine whether CD40 acts as a costimulatory molecule on T cells from T1D patients. Because T cells play a major role in the initiation and progression of type 1 diabetes, a biomarker of autoreactive T cells in T1D would be of great value in diagnosis of human patients. Most importantly, understanding why and how T cells signal through CD40 in an autoimmune response may provide new avenues to therapy in humans.

Researcher Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes? 

This project is a basic research project to investigate underlying causes of the autoimmune process that characterizes type 1 diabetes (T1D). Specifically, our goals are to determine how a signaling molecule called CD40 contributes to T cell pathogenicity in the NOD mouse model of autoimmune diabetes and whether CD40 can also act as an amplifier of the autoimmune response in human type 1 diabetes. We will be using the NOD mouse model to determine whether inhibition of cellular signaling through the CD40 molecule can inhibit disease and how this happens. We will also be investigating whether CD40 acts as a signaling molecule on T cells from T1D patients.

Because T cells play a major role in the initiation and progression of disease, identification of a biomarker on autoreactive T cells in T1D could be of great value in diagnosis of human patients. Most importantly, understanding why and how T cells signal through CD40 in an autoimmune response may provide new avenues to therapy in humans.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

Since much of the autoimmune disease process in T1D is governed by autoreactive T cells, understanding the mechanisms by which these T cells contribute to disease and how they can be regulated is of key importance to coming up with intelligent new approaches to therapy. It has been known for some time that inhibiting interaction between the CD40 signaling molecule and the molecule on activated T cells to which it binds, can prevent disease. However, initial procedures to inhibit this interaction were found to be unsuitable for human therapy and therefore, new strategies need to be devised. The finding by our group that CD40 is uniquely expressed on autoreactive T cells provides a new opportunity to discover not only how this molecule contributes to pathogenesis of T1D, but also how it might be exploited for targeted immunotherapy. 

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?  

I am not diabetic nor are members of my family. However, I have been associated with the Barbara Davis Center for Childhood Diabetes for many years, first as a newly appointed faculty member and currently in collaborative research. From a personal standpoint, I have had several technicians, students, and fellows in my laboratory - including two at present - who are type 1 diabetics. Thus over the course of my career, I have had contact with many diabetics and health practitioners who treat diabetics. As an immunologist, I am particularly interested in the autoimmune aspects of type 1 diabetes, especially the underlying causes of pathogenesis and how the process is regulated. This award will allow us to continue and move forward with a project in which we have made exciting new progress over the last two years. 

In what direction do you see the future of diabetes research going? 

There is little doubt that one very active area of diabetes research will continue to be centered on how to overcome the problems of autoimmunity, both in terms of understanding progression of disease and with respect to immunosuppression in islet transplantation. Basic research in the immunology of this disease is fundamental to coming up with a cure for diabetes. We need to understand not just what happens when transplants are rejected, but every aspect of the disease process: how it develops, what are the triggers, what are the molecular players in the immune system, and how we overcome the autoimmune response. Therefore, the future of diabetes research needs to involve a broad, multi-faceted approach, especially since discoveries in one place often have implications for work in other areas.