The heterogenous family of CD4+ T effector cells

Sergio Romagnani University of Florence, Italy

CD4 + T cells are a heterogenous family of cells, some of which exerting an effector activity for protection against esogenous antigens, and some devoted to control immune response against self and also to dampen effector responses against exogenous antigens when they become dangerous for the body. Initially, two polarized types of CD4+ T effector cells were identified in mice and humans that were names as type1 (Th1) or type 2 (Th2). Th1 cells produce mainly IFN-g and are responsible for protection against intracellular bacteria and some viruses, whereas Th2 produce IL-4, IL-5, IL-9 and IL-13, which exert some protective effect against parasites. There are reciprocal regulatory effects between the two subsets, inasmuch as IFN-g inhibits Th2 development, whereas IL-4 inhibits Th1 development. Th1 and Th2 cells have also distinct and mutually inhibitory transcription factors, STAT-4 and T-bet being specific for Th1 cells, whereas STAT-6, GATA-3 and c-maf are selectively expressed by Th2 cells. Th1 and Th2 also express distinct chemoattractant receptors, like CXCR3 for Th1, and CCR3, CCR4, CCR8 and CRTH2 for Th2, that allow selective recruitment of the two cell types in the target tissues. Recently, we have shown that there are two distinct CXCR3 receptors (CXCR3-A and CXCR3-B), the first interacting with the chemokines CXCL9, CXCL10 and CXCL11 and second also showing high affinity for CXCL4. Interestingly, CXCL10 mainly favors the production of Th1 cytokines, whereas CXCL4 promotes the production of Th2 cytokines, thus providing another counter-regulatory pathway between the two cell subsets. Th1 cells originate when Toll-like receptors (TLR) on dendritic cells (DC) are activated by microbial products that induce their maturation and the production of IL-12, whereas the early production of IL-4 is required for Th2 polarization. Recently, we have shown that human immature myeloid DC polarize the response of CD4+ T cells towards the Th2 phenotype through the interaction between their ligand Jagged-1 and the NOTCH receptor expressed on T cells. By contrast, triggering of TLR on DC induces their maturation, a strong up-regulation of their ligand Delta-4, the production of IL-12 and CXCL10, and the Th1 polarization. More recently, a third type of effector CD4+ T cells has been described in mice and named as Th17. These cells express a transcription factor different from that of Th1 or Th2 cells (RORgt), produce IL-17, IL-21, IL-22, as well as the neutrophil-recruiting chemokine CXCL8, which play a role in the protection against extracellular bacteria and are responsible for different murine models of autoimmune disorders or other chronic inflammatory disorders, such as the collagen-induced arthtritis, the experimental autoimmune encephalomyelitis and the bowel inflammatory disease. In mice, Th17 cells originate in response to the combined production of IL-6 and TGF-b and are maintained and/or expanded by IL-23 and IL-21, whereas in presence of TGF-b alone (without IL-6) the same CD4+ T cells develop into T regulatory (Treg) Foxp3+ T cells. In humans, however, the situation seems to be different. We have recently shown that human Th17 cells always co-exist in blood and tissues with T cells producing both IL-17 and IFN-g (Th17/Th1) and at clonal level both these cell types express both RORgt and T-bet, as well as high levels of IL-23 receptor (IL-23R) and CCR6. Moreover, they induce production of IgM, IgG and IgA, but not IgE, by B cells, but show little cytotoxic potential and appear to be less susceptible than Th1 or Th2 cells to the suppressive activity of an autologous Fop3+ Treg clone. More recently, we have found that both Th17 and Th7/Th1 cells can originate from umbilical cord blood (naïve) CD4+ T cells only in presence of a combination of IL-23 and IL-1. IL-23 induces RORgt and T-bet expression and both cytokines up-regulate the IL-23R and induce the expression of IL-17 mRNA and the production of IL-17. Again, part of these cells produce IL-17 alone and part of them IL-17 plus IFN- g. Accordingly, the addition of IL-12 to the combination of IL-23 and IL-1 shifts virtually all CD4+ T cells to produce IFN-g alone. By contrast, TGF-b indirectly potentiates the Th17-inducing activity of IL-23 and IL-1 because Th17 seem to be much less susceptible than Th1 or Th2 cells to its anti-proliferative effect. Taken together, these results suggest that, at least in humans, Th17 and Th1 cells seem to have a common developmental origin.