Can helper T-17 cells play a role in dengue haemorrhagic fever?

Indian Journal of Medical Research, July, 2009 by Nivedita Gupta, U.C. Chaturvedi

Dengue virus (DV) infection produces epidemics of a mild acute febrile illness, dengue fever (DF) that may progress to a life threatening severe illness, dengue haemorrhagic fever (DHF). DHF is the most important arbovirus disease in man and the frequency of dengue epidemics has markedly increased with expansion to newer geographical areas. Understanding the factors that are involved in the pathogenesis of DHF continues to be one of the most active area of dengue research. It has been established that DHF is caused by a "Cytokine Tsunami" but despite extensive studies for over four decades, its genesis is still not fully understood. Any time a possibility appears in the horizon, attempt is made to fit it in the scheme of events in DHF somewhat akin to the Indian anecdote of twelve blind persons trying to figure out an elephant. The mechanisms that have been considered to cause DHF include, antibody-dependent enhancement (ADE) of infection, dengue virus NS 1-antibodies cross-reacting with vascular endothelium (a type of autoimmune phenomenon), immune complex disease, complement and its products, memory T cells, various soluble mediators including cytokines resulting in "Cytokine Tsunami", selection of virulent strains and virus virulence, etc. (1-5). A new entity that is knocking at the door of DHF research is helper T cell-17 (Th17 cells) that deserves serious consideration and investigation both, in man and mouse infection with DV. We have discussed here why it may be worthwhile to direct attention of the dengue virologists/immunologists to the Thl7 cells.

Helper T cells

More than two decades back Mosmann et al (6) classified the fully differentiated CD4[sup. ] helper T (Th-cells into two major subsets depending upon their cytokine secretion pattern that correlated well with the distinctive functions of these cells. The Th-1 cells secrete interferon-gamma (IFN-[alpha]), interleukin-2 (IL-2) and tumour necrosis factor-beta (TNF-[beta]) and are responsible for cell-mediated inflammatory reactions, delayed type hypersensitivity and tissue injury in infections and autoimmune diseases. The Th-2 cells secrete IL-4, IL-5, IL-6, IL-10, and IL-13 and are associated with help for B cell antibody production. Infections with a dominant humoral immune response induce a higher expression ofTh2-related cytokines and those characterized by delayed type hypersensitivity response show a higher expression of Thl cytokines. Thl cells eradicate pathogens, but may also cause immunopathology. This adverse effect is minimized by anti-inflammatory cytokine IL-10 which suppresses the production of proinflammatory cytokines by dendritic cells and macrophages, including IL-12, thereby inhibiting the ability of antigen-presenting cells to induce differentiation of Thl cells. IL-10 was originally isolated from Th2 cells, it is now known to be produced by many cell types, e.g., monocytes, macrophages, dendritic cells, B cells, CD8 T cells, regulatory T cells, Thl cells and Thl7 cells. The main role of IL-10 appears to contain and suppress inflammatory responses, thus to downregulate effector adaptive immune responses and minimize tissue damage in response to microbial infection(3,7,8). In a number of viral infections such as dengue, human immunodeficiency, herpes simplex and influenza viruses, a Thl response is linked to recovery from infection while a Th2-type response leads to severe pathology and exacerbation of the disease (6). The Thl-Th2 paradigm was a simple classification that served well in a number of situations so far but left a number of aspects unexplained.

Th 17 cells

Recently, a third lineage of CD4 helper T cells, the Thl7 cells have been described that secrete mainly IL-17. The naive CD4 T cells differentiate into distinct Thl7 cell in response to combined signals from transforming growth factor (TGF)-beta, IL-6, IL-21, IL-1 beta and IL-23. Further, IL-1 alpha or IL-1 beta along with IL-23 can promote IL-17 secretion from memory T cells. The induction/functions of Thl7 cells are regulated by cytokines secreted by the other major subtypes ofT cells, including IFN-gamma, IL-4, IL-10 and at high concentrations, TGF-beta. Fig. 1 shows the differentiation of naive T cell into the three different T helper cell types i.e., Thl, Th2 and Thl7, based on the cytokine stimulus received. Thl7 cells are a distinct linage from Thl or Th2 cells; the transcriptional factor ROR-yt directs development of Th17 cells, while T-bet and GATA3 induce the development of Thl and Th2 cells, respectively, and inhibit differentiation of Thl 7 cells. The main function of IL-17-secreting T cells is to mediate inflammation, by stimulating production of inflammatory cytokines, such as TNF-alpha, IL-1beta and IL-6, and inflammatory chemokines, including CXCL-6, CXCL-7, CXCL-8, IL-8 and monocyte chemoattractant protein-1 (MCP-1), and metalloproteinases that promote the recruitment of neutrophils and macrophages (recruited by Thl cells) resulting in inflammation and tissue pathology (Fig. 2). IL-17-producing T cells play a key role in the pathogenesis of organ-specific autoimmune diseases, and together with Thl cells mediate protective immunity to pathogens. Besides the Thl7 cells, IL-17 is also secreted by CD8 T cells, [chi][delta] T cells and natural killer T (NKT) cells (7,9,10).