The adverse consequences of inappropriate cross-regulation of effector T-cell responses by cytokines have been demonstrated in a number of infectious models in mice. Such studies reinforce the notion that induction of the appropriate effector CD4 T-cell subset is crucial for pathogen clearance, and show that subtle differences in CD4 T-cell responses can have a significant impact on the outcome of infection. One example of this is the murine model of infection by the protozoan parasite Leishmania major, which requires a TH1 response and activation of macrophages for clearance. C57BL/6 mice produce TH1 cells that protect the animal by activating infected macrophages to kill
L. major. In BALB/c mice infected with L. major, however, CD4 T cells fail to differentiate into TH1 cells; instead, they become TH2 cells, which are unable to activate macrophages to inhibit Leishmania growth. This difference seems to result from a population of memory T cells that are specific for gut-derived antigens but cross-react with an antigen, LACK (Leishmania analog of the receptors of activated C kinase), expressed by the Leishmania parasite. These memory cells are present in both strains of mice, but for unknown reasons they produce IL-4 in BALB/c mice but not in C57BL/6 mice. In BALB/c mice, the small amount of IL-4 secreted by these memory cells during Leishmania infection drives new Leishmania-specific CD4 T cells to become TH2 cells instead of TH1 cells, leading to failure of pathogen elimination and death. The preferential development of TH2 rather than TH1 cells in BALB/c mice can be reversed if IL-4 is blocked early during infection by anti-IL-4 antibody, but this treatment is ineffective after a week or so of infection, demonstrating the crucial importance of cytokines early in developmental decisions made by naive T cells (Fig. 9.35).
9-23 Regulatory CD4 T cells are involved in controlling adaptive immune responses.
Regulatory T cells play a central role in preventing autoreactive immune responses and fall into different groups that are defined by their different developmental origins and functions. Natural T-regulatory (nT ) cells develop in the thymus (see Section 8-26) and are CD4-positive cells that constitutively express CD25 and high levels of the L-selectin receptor CD62L and of CTLA-4. Induced T (iT ) cells arise in the periphery from naive CD4 T cells and also express CD25 and CTLA-4 (see Section 9-20). Collectively, T cells represent about 5–10% of the CD4 T cells in circuation. A hallmark of both natural and induced T cells is expression of the transcription factor FoxP3, which, among other actions, interferes with the interaction between AP-1 and NFAT at the IL-2 gene promoter, preventing transcriptional activation of the gene and production of IL-2.