IL-10 production by CD4+ effector T cells: a mechanism for self-regulation

Abstract

The development of Th1 lymphocytes is essential for cell-mediated immunity and resistance against intracellular pathogens. However, if left unregulated, the same response can cause serious damage to host tissues and lead to mortality. A number of different paracrine regulatory mechanisms involving distinct myeloid and lymphoid subpopulations have been implicated in controlling excessive secretion of inflammatory cytokines by Th1 cells. Much of this work has focused on interleukin (IL)-10, a cytokine with broad anti-inflammatory properties, one of which is to counteract the function of Th1 lymphocytes. While studying the role of IL-10 in regulating immunopathology during infection with the intracellular parasite Toxoplasma gondii, we discovered that the host-protective IL-10 derives in an autocrine manner from conventional interferon-gamma (IFN-gamma)-producing T-bet(+) Foxp3(neg) Th1 cells. In the following review, we will discuss these findings that support the general concept that production of IL-10 is an important self-regulatory function of CD4(+) T lymphocytes.

Figure 1. Stable vs. conditional expression of IL-10 in Th effector subsets

Antigen-activated naïve CD4⁺ T lymphocytes can adopt at least 3 distinct effector phenotypes as directed by cytokines within the local environment. In the presence of IL-4 they differentiate into Th2 cells, which in addition to IL-4, −5 and −13 also stably express IL-10 (without the requirement for IL-4 instruction during subsequent stimulation). IL-12 promotes Th1 differentiation by inducing IFN-γ synthesis. While Th1 lymphocytes can also express IL-10, their production of the cytokine is not stable. Likewise, Th17 effectors, generated in the presence of IL-6 and TGFβ and characterized by IL-17 expression (with or without IL-22) can secrete IL-10 under the correct set of conditions.

Figure 2. Extracellular signals and intracellular pathways regulating expression of IL-10 gene in Th1 and Th17 cells

A. The diagram depicts 4 different mechanisms of IL-10 induction in Th1 cells proposed in the literature and discussed in this review. While not mutually exclusive, they together reveal the involvement of extracellular factors such as Ag concentration, the cytokines IL-12 and IL-27, as well as expression of Notch and ICOS ligands on DC. In each mechanism, distinct Signal Transducers and Activators of Transcription (STAT) proteins and/or intracellular signaling cascades have been implicated suggesting that IL10 expression in Th1 cells may be achieved though multiple non-redundant pathways. Nevertheless, in each case our incomplete understanding of the down-stream DNA-binding regulatory elements that determine IL-10 gene activation (as indicated with question marks) leaves open the possibility for an as undefined unifying mechanism. B. In Th17 cells expression of IL-10 can be induced by IL-6, IL-21 and IL-27, which all signal through STAT3. Interestingly, IL-6 and IL-21 are known to promote Th17 differentiation, whereas IL-27 inhibits the development of Th17 cells. While STAT3 may play a critical role, it is not yet clear whether additional signaling pathways known to be activated by each of three cytokines contribute to conditional IL-10 expression. Nevertheless, the transcriptional factor c-maf, which binds to the MARE sequence in the IL-10 promoter, appears to be a common component in all three pathways suggesting a consensus mechanism of IL-10 expression in Th17 effectors that is currently lacking for Th1 lymphocytes (see A above).