Roles for helper T cell lineage-specifying transcription factors in cellular specialization

The development of specialized helper T cells has garnered much attention because of their critical role in coordinating the immune response to invading pathogens. Recent research emphasizing novel functions for specialized helper T cells in a variety of infectious disease settings, as well as autoimmune states, has reshaped our view on the capabilities of helper T cells. Notably, one previously underappreciated aspect of the lifespan of helper T cells is that they often retain the capacity to respond to changes in the environment by altering the composition of helper T cell lineage-specifying transcription factors they express, which, in turn, changes their phenotype. This emerging realization is changing our views on the stability versus flexibility of specialized helper T cell subtypes. Now, there is a new concerted effort to define the mechanistic events that contribute to the potential for flexibility in specialized helper T cell gene expression programs in the different environmental circumstances that allow for the re-expression of helper T cell lineage-specifying transcription factors. In addition, we are also now beginning to appreciate that "helper T cell" lineage-specifying transcription factors are expressed in diverse types of innate and adaptive immune cells and this may allow them to play roles in coordinating aspects of the immune response. Our current challenges include defining the conserved mechanisms that are utilized by these lineage-specifying transcription factors to coordinate gene expression programs in different settings as well as the mechanistic events that contribute to the differential downstream consequences that these factors mediate in unique cellular environments. In this review, we will explore our evolving views on these topics, often times using the Th1-lineage-specifying transcription factor T-bet as an example.