Follicular Homing T Helper (Th) Cells and the Th1/Th2 Paradigm

The Th1/Th2 paradigm is a cornerstone for our understanding of T cell responses (1). It conveniently subdivides T cell immune responses into those specialized for defense against intracellular pathogens including viruses and some bacteria (Th1), and a second for defense against large extra-cellular pathogens such as helminths. Th1 responses depend on IL-12 and IFN-␥ to mediate a range of biological effects designed for antiviral immunity. In contrast, Th2 responses employ the cytokines IL-5, IL-4, and IL-13, which promote the mobilization of eosinophils and cause other in-flammatory processes designed to expel large parasites. The Th1/Th2 paradigm also has particular relevance for certain inflammatory diseases, as asthma is essentially a Th2 response gone awry, and many autoimmune diseases depend on a Th1 response to autoantigens. However, this neat scheme had one troubling aspect: where do helper cells for antibody production fit in? T cell help for antibody production has long been considered a Th2 property (2, 3), although certain Ig class switching relies on IFN-␥. As acceptance of the Th1/Th2 paradigm increased among immunologists, so too has the effort to identify Th1-or Th2-associated genes or molecules. Numerous transcription factors/signal transducers such as T-bet, signal transducer and activator of transcription (Stat)-6, GATA-3, and Stat-4 were identified that determined Th1 or Th2 differentiation and function (4–6). In mice deficient in Stat-6, a Th2 transcription factor, IL-4 signaling is abolished and Th2 responses are absent. Nevertheless, these mice are still capable of mounting T cell–dependent antibody responses (although not IgE, an isotype for mast cell activation). The discovery of the various Th1-and Th2-related transcription factors cemented the validity of the Th1/Th2 paradigm , but what remained unclear was the precise role of Th1 cytokine–producing, or Th2 cytokine–producing cells in different immune responses. Cell surface molecules that reliably mark Th1 or Th2 cells were also sought, and to date the chemokine receptors are probably the most convenient (although by no means ideal) markers of functional subsets. Th1 cells preferentially express CC chemokine receptor (CCR)5 and CXC chemokine receptor (CXCR)3, and migrate in response to a select set of chemokines induced by cytokines such as IFN-␥ or IL-1, whereas Th2 cells preferentially express CCR3 and CCR4 and migrate to chemokines induced by IL-4 or IL-13 (7–12). The regulated expression of chemokine receptors by effector T cells relates to the simple concept that migration or positioning of a cell is intimately connected to that cell's function (11). In …