Imbalance in Th cell polarization and its relevance in type 1 diabetes mellitus

Abstract

Functional polarization of T helper (Th) subsets of lymphocytes has been implicated in promoting or conferring risk to Type 1 diabetes mellitus (T1DM) development in human and diabetic animal models. It is assumed that an immoderate preponderance of type 1 immunity establishes the prerequisite for this development. Over the past years, various immune-intervention strategies have been tested to protect diabetic animals from developing overt diabetes. These protocols implicate a protective mechanism that is attributed to a change in the set of autoreactive Th cells from their Th1 to the Th2 phenotype. The studies were aimed at improving the effectiveness of Th2 cells to secrete the principal cytokines, IL-4 and IL-10, in order to mediate protection from diabetes in NOD mice. In contrast, some immune-modulation protocols utilizing non-specific reagents report that diabetes protection is apparently attributed to preferential survival of both Th1 and Th2 cells, rather than via a shift from their Th1 to Th2 phenotypes. Even though we know that excessive immune responses against self antigens are also controlled and terminated by regulatory T cells, this article focuses on the polarization of Th effector cells and discusses the controversial findings regarding the Th1/Th2 hypothesis to draw a conclusion on its relevance in T1DM from the existing knowledge.

Figure 1. Th cell polarization

Polarization towards Th1 is achieved via antigen recognition of a naive T cell by its TCR together with a costimulation signal provided by B7-1 and B7-2. In contrast, Th2 activation heavily relies on costimulatory engagement of ICOS and ICOSL. APCs support Th1(Th2) cell polarization by releasing IL-12 (IL-6). Upon Th1 (Th2) cell activation these cells secrete IFN-γ (IL-4) to stimulate APCs to secrete more IL-12 (IL-6). IFN-γ secretion by Th1 cells also inhibits Th2 cell activation. Th2 cells in turn can secrete IL-10 to suppress the activation of Th1 cells. In addition, cytokine secretion by Th2 cells activates B cells to produce antibodies.