CD4+ T helper subsets. CD4+ T cells can differentiate into different subsets depending on the cytokine milieu present during T cell activation. TH1 cells, activated in the presence of IL-12 and IL-18 produced by activated DCs, make IFNγ, which is important in activating macrophages to kill intracellular bacteria, such as M. tuberculosis. IL-4 made by TH2 cells activates macrophages to expel parasites (the cellular source of the IL-4 that promotes TH2 development is currently poorly defined). T follicular (Tfh) cells can make the canonical cytokines that TH1 or TH2 cells produce, but they also make IL-21 and express cell-surface molecules, such as CD40 ligand and inducible T cell co-simulator (ICOS), that are required for effective B cell responses and production of high-affinity, class-switched antibodies. The more recently described TH17 cells can produce IL-17 and IL-22 and are generated in the presence of IL-6 and TGFβ. IL-17 and IL-22 are important for promoting the influx of neutrophils to inflamed sites and the production of antimicrobial peptides, respectively. TH17 cells are thought to be important in defense against extracellular bacteria and fungi. Activated T cells can also differentiate into regulatory T cells (Tregs) in the presence of TGFβ and/or retinoic acid (RA). These cells can inhibit and control immune responses to prevent excessive inflammation through cell-surface molecules (such as CTLA-4) or cytokines, such as IL-10.