CD4+ T Cell Differentiation in Infection: Amendments to the Th1/Th2 Axiom

CD4 T helper (Th) lymphocytes play a central role in orchestrating immune responses. While the specificity of naïve CD4 T cells is fixed and constrained by the TCR they express, their effector potential is flexible and unbiased. After antigen encounter, Th lymphocytes acquire a specific effector function by responding to the summation of input signals provided by antigen-presenting cells (APC) and cytokine microenvironment. The functional diversity of Th cells provides the immune systemwith the capacity tomount an appropriate defensemechanism against various types of pathogens. The initial discovery of the existence of specialized Th effector populations came from an analysis of mouse CD4 T cell clones by Mosmann and Coffman (1). This seminal study demonstrated that differentiated CD4 T cells can be classified into two groups, designated Th1 and Th2 cells, based on their cytokine production. Th1 lymphocytes, which are defined by secretion of IFN-γ, TNF, and IL-2, promote cell-mediated immunity and control infections with intracellular pathogens. In contrast, Th2 lymphocytes, which produce IL-4, IL5, IL-10, and IL-13, mediate humoral immune responses and resistance to helminth parasites. In addition, the Th1/Th2 dichotomy was also demonstrated in immunopathological settings where Th1 and Th2 cells are implicated in autoimmune diseases and allergic conditions, respectively. The recognition that different CD4 T cell subsets are associated with specific outcomes in both infection diseases and immune disorders propelled research into the Th1/2 paradigm. Generation of mature Th effectors was defined as an endpoint of amultistep lineage-specific differentiation process in which naïve CD4 T lymphocytes gain the ability to produce exclusively Th1 or Th2 cytokines. Moreover, a similar concept of dichotomous Th1/2 immune functions has been put forward for other lymphocyte populations (Tc1/Tc2), as well as other types of immune cells such asmacrophages (M1/M2) and dendritic cells (DC1/DC2). However, significant technical advances in CD4 T cell biology research over past 20 years have revealed that the Th1/Th2 paradigm cannot fully explain the complexity of Th effectors and led to the discovery of new Th subsets that have distinct yet overlapping functions with Th1/Th2 cells (2–4). For example, Th17 cells, which produce IL-17, are important in controlling extracellular bacterial and fungal pathogens, but can also promote autoimmune disorders (5, 6). Similarly, Tfh cells, which produce IL-21, are important for germinal center formation and antibody production, have taken on some of the functions originally attributed to Th2 cells (7, 8). Together, these findings clearly challenge Th1/2 concept and the model of Th effector choice as a bidirectional and linear differentiation process. Indeed, newmolecular techniques that enable comparative analysis between genome-wide landscape of different transcriptional factors and cell-specific transcriptional output