CD4+ T cells that secrete IL-17 (Th17 cells) play a pathogenic role in many autoimmune diseases, but also function with Th1 cells to mediate protective immunity to infection by promoting recruitment and activation of neutrophils and macrophages respectively. Stimulation of dendritic cells by pathogen-derived molecules promotes maturation and the production of T-cell differentiating cytokines. We have shown that TLR and NLR agonists induce innate IL-1 and IL-18 which synergize with IL-23 to activate memory Th17 cells, but also IL-17 production by γδ T cells without TCR engagement.

TLR signalling also leads to IL-12 production, which promotes induction of Th1 cells. Consequently TLR agonists are effective adjuvants for vaccines against infectious disease. We have demonstrated that TLR2 or TLR9 agonists are potent adjuvants for an acellular pertussis vaccine (aP) and considerably enhance its efficacy over the currently licensed aP which is administered with alum as the adjuvant. Whooping cough is a re-emerging infectious disease and the current aP induces Th2 and Th17 responses, but weak Th1 responses. Interestingly, Th2 responses were redundant and protection with alum-adjuvanted aP is mediated by Th17 cells, driven by alum-activated IL-1β. In contrast, immunization with an aP formulation containing a novel TLR2 lipopeptide from Bordetella pertussis or a TLR9 agonist induced strong Th1 and IgG2a responses and a high level of protection against respiratory infection with B. pertussis. 

In the field of autoimmunity, much of the focus in drug discovery has been on IL-17A production by CD4⁺ Th17 cells and its induction by IL-23. However CD8⁺ T cells, gd T cells, NKT cells and other innate lymphoid cells are all capable of secreting IL-17A. There is also evidence that other cytokines, including IL-17F, GM-CSF, IL-21 and IL-22, are produced by Th17 and IL-17A-secreting innate immune cells. Furthermore, the role of IFN-γ, secreted by Th1, NK and type 1 innate lymphoid cells (ILC1) cells, is still unclear, with some evidence that IFN-γ is protective in autoimmunity by inhibiting Th17 cells. However, we have demonstrated in experimental autoimmune encephalomyelitis, a mouse model for multiple sclerosis, that early NK cell-derived IFN-γ plays a pathogenic role through activation of M1 macrophages and VLA4 expression on T cells, required for their migration into the CNS.   

The induction and function of Th1 and Th17 cells is regulated by cytokines secreted by the other major subtypes of T cells, especially IL-10 and TGF-β production by Treg cells but also by regulatory cells of the innate immune system. The induction of adaptive Treg cells is stimulated by retinoic acid, TGF-β and IL-10 in response to certain virulence factors from pathogens, such as helminth parasites that have evolved sophisticated mechanisms to subvert host protective immunity. Pathogens and pathogen-derived molecules can also promote activation of alternatively activated M2 macrophages, ILC2 and tolerogenic dendritic cells that can suppress Th1 or Th17 cells, either directly or through the induction of Treg cells. We have identified approaches for activation of anti-inflammatory cytokines, regulatory innate immune cells and Treg cells, without Th1 or Th17 cells. These approaches have been effective in attenuating inflammatory disease in pre-clinical models of autoimmunity.