Abstract
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.
Highlights
Specialty section: This article was submitted to Diabetes, a section of the journal Frontiers in Endocrinology
These findings indicate that when CD40 levels are sufficiently controlled, effector cells are able to express FOXP3
Numerous studies demonstrate that negative selection failure gives rise to peripheral pathogenic T cells
Summary
Given that the Immunoglobulin family (CD28/ICOS ) knockouts still experienced classic T cell responses; the only viable explanation was “other” costimulatory molecules. Members of the TNFRSF that act as T cell costimulatory molecules include 4-1BB and OX40 Both OX40 and 4-1BB are activation induced and promote cell survival, potential T cell memory formation, and cytokine production [69,70,71]. CD40 expression has been described on endothelial cells [105]; neural cells [106]; and surprisingly on islet β cells [107,108,109] On each of those cell types, CD40 engagement leads to pro-inflammatory cytokine production. In NOD female mice that did not develop diabetes, TH40 cell numbers remain at numbers found in non-autoimmune mice These observations suggest that breach of tolerance involves TH40 cell number expansions. Observations further show that in diabetes prone NOD mice expression of CTLA-4 is deficient [39]
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