Development of Type 1 Diabetes Immunity Cells

Type 1 Diabetes (T1D) develops when immune cells invade the pancreatic islets resulting in loss of insulin production in beta cells. T cells have been proven to be central players in that process. What is surprising, however, is that classic mechanisms of tolerance cannot explain diabetogenesis; alternate mechanisms must now be considered. T cell receptor (TCR) revision is the process whereby T cells in the periphery alter TCR expression, outside the safety-net of thymic selection pressures. This process results in an expanded T cell repertoire, capable of responding to a universe of pathogens, but limitations are that increased risk for autoimmune disease development occurs. Classic T cell costimulators including the CD28 family have long been thought to be the major drivers for full T cell activation. In actuality, CD28 and its family member counterparts, ICOS and CTLA-4, all drive regulatory responses. Inflammation is driven by CD40, not CD28. CD40 as a costimulus has been largely overlooked. When naïve T cells interact with antigen presenting cell CD154, the major ligand for CD40, is induced. This creates a milieu for T cell (CD40)–T cell (CD154) interaction, leading to inflammation. Finally, defined pathogenic effector cells including TH40 (CD4⁺CD40⁺) cells can express FOXP3 but are not Tregs. The cells loose FOXP3 to become pathogenic effector cells. Each of these mechanisms creates novel options to better understand diabetogenesis and create new therapeutic targets for T1D.

Medical advances in infectious diseases have been extraordinary, completely changing human history. The polio vaccine, small pox vaccine, and measles vaccine among others changed modern medicine. Success with infectious diseases has influenced and created a generalized approach to most medical problems. Unfortunately, using that approach for autoimmune disease has fared much less well. Diseases like type 1 diabetes (T1D) and multiple sclerosis (MS) have seen unpredictable and steady increases in incidence over the last half-century, with only limited treatment options and no cure options on the horizon.

Regards

John
Editorial Assistant
Pancreatic Disorder and Therapy