JAK/STAT signaling in T cells lineage decision.
The immune response against invading microbes and tissue injuries results in inflammation, a complex physiological response that comprise:
- Cytokine production
- Cell trafficking
- Mediator production
In addition to the classical inflammation elicited by infections, also allergic and autoimmune reactions are facet to inflammatory response, and these pathological abnormalities well exemplify the need of a tight regulation in these responses.
Indeed, a huge number of cytokines and hormones controls the concerted action of cells executing the inflammatory response. The role of cytokines is to regulates the proliferation and differentiation status of cells triggering signaling pathways that modulates gene expression in order to promote or suppress the inflammatory reaction.
One of this pathway is the JAK/STAT, which tight regulation is important in controlling cytokine response, as schematically present in the poster from Invitrogen web site.
Lineage decision of T cell subsets.
Engagement of the T cell receptor (TCR) by the appropriate peptide-major histocompatibility complex (MHC) in context with cytokines and costimulatory molecules clonal expansion of Th cells, which rapidly differentiate into at least two funtional classes of cells, named Th1 and Th2.
Th1 response is essential for resistance to most bacteria, intracellular protozoa and fungal pathogens, this cell type can also mediate organ-specific autoimmunity and are critical for pathogenesis of some autoimmune diseaes such as rheumatoid arthritis, mellitus diabetes and multiple sclerosis. Th1 lymphocytes primarly secrete pro-inflammatory effetcor cytokines like IFN-gamma and TNF-β that regulate signaling important to promote cell-mediated immunity and control intracellular pathogens.
Th2 cells in contrast secrete anti-inflammatory cytokines (IL-4, IL-5, IL-9, IL-10, IL-13) supporting the humoral immune response, which is important in host defense against intestinal helminthes. This cell type has been implicated in the pathogenesis of asthma and allergy, on the contrary Th2 cytokines can inhibit autoimmune disease by constraining cell-mediated immunity.
There are many factors that can contribute to the decision to become a Th1 or Th2 cell, and IL-12 and IL-4 are key determinant in this process. In particular IL-12 activates Stat4 and commit the cell to a Th1 fate, while IL-4, trought the activation of Stat6 pathway mediate the differentiation of Th2 cell. Moreover the products of Th1 and Th2 cells, IFN-gamma and IL-4, respectively, promote commitment to their respective lineages and inhibit development of the opposing lineage.
The biology of Stat4 and Stat6.
Another subset of CD4+ T cells are now known to have additional fates regulated by Stat3 and Stat5.
Treg: one subset is termed regulatory T cells, which express the transcriptional factor Foxp3, this cell type has essential immunosuppressive functions as illustrated by the fact that deletion or mutation of Foxp3 leads to fatal autoimmune disease in mice and humans. Treg cells can be generated in the thymus or can be induced in the periphery, but in both cases cytokines that use the gc are important drivers of their development. Deficiency of Stat5 leads to loss of Treg cells and inability to induce Treg cells in vitro, whereas constitutive activation of Stat5b enforces Foxp3 positive Treg cells development (bypassing the upstream cytokine stimulation).
Th17: another fate for CD4+ T cells is the Th17 cell, whose development and function is critical dependent on Stat3. So named for their ability to produce the inflammatory citokyne IL-17, the Th17 cells recruit and activate neutrophils and other inflammatory cells to the inflammation site. So Th17 cell fate, to which IL-6 contribute, their peripheral maintenance by IL-21 and their effector function, also trought IL-23, are all regulated by Stat3 signaling from different cytokine receptors.
Thus the balance of Treg and Th17 cell differentiation appears to be regulated by Stat5 and Stat3.
New insights into the roles of Stat5a/b and Stat3 in T cell development and differentiation..