Regulatory T cells in Parasite Infection

Since 2005, a series of key findings have demonstrated that Tregs play a major part in the immunology of helminth infections. Our work with Matt Taylor showed that depletion/neutralisation of Tregs in vivo during Litomosoides sigmodontisinfection, results in greater clearance of parasites and recovery of immune function among anergised effector populations (Taylor et al., 2005, 2007, 2009). These studies, together with evidence for high Treg activity in chronic human filarial infections (Babu et al 2006, 2009), suggest that the regulatory T cell population is responsible for the steady-state unresponsiveness in long term infection, and that targetting the Treg subset may be a rational strategy to effect an immunological cure.

We also demonstrated that mice infected with H. polygyrus generate a "hyperactive" Treg population (Finney et al 2007) which, on transfer to an allergic but parasite-naive mouse, would suppress airway allergy (Wilson et al 2005). The "bystander" effect of parasite-induced Tregs inhibiting an antigenically-unrelated response (to either ovalbumin or Der p 1 allergen) provides a mechanistic explanation for the "Hygiene Hypothesis".

Most recently, we have shown that both B. malayi (McSorley et al 2008) and H. polygyrus infections can induce expression of Foxp3 in DO11.10 ovalbumin-specific transgenic T cells, and further that secreted protein from H. polygyrus can exert the same effect. Hence, the activation of a regulatory T cell network in infection cannot simply be attributed to a host homeostatic mechanism that may normally accompany every activated effector response. Rather, Treg induction appears to be part of the parasite's own strategy to survive in the host.

Questions

The questions we now plan to ask include:

• Are Tregs specific for parasite antigens induced?

• Are either natural or induced Tregs essential for parasite survival in vivo?

• Do Tregs convert from Th0 or Th2 cells in infection, and can they switch (back) to effector Th2 cells?

• Which are the best interventions to cure infection - to block initial Treg induction, or to reverse Treg activity later in infection?

References

Babu, S., Blauvelt, C.P., Kumaraswami, V., Nutman, T.B. (2006) Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence. J Immunol 176, 3248-3256.

Babu, S., Bhat, S.Q., Pavan Kumar, N., Lipira, A.B., Kumar, S., Karthik, C., Kumaraswami, V., Nutman, T.B. (2009) Filarial lymphedema is characterized by antigen-specific Th1 and th17 proinflammatory responses and a lack of regulatory T cells. PLoS Negl Trop Dis 3, e420

Finney, C.A., Taylor, M.D., Wilson, M.S., Maizels, R.M. (2007) Expansion and activation of CD4+CD25+ regulatory T cells in Heligmosomoides polygyrus infection. European Journal of Immunology 37, 1874-1886.

McSorley, H.J., Harcus, Y.M., Murray, J., Taylor, M.D., Maizels, R.M. (2008) Expansion of Foxp3+ regulatory T cells in mice infected with the filarial parasite, Brugia malayi.. Journal of Immunology 181, 6456-6466.

Taylor, M., Le Goff, L., Harris, A., Malone, E., Allen, J.E., Maizels, R.M. (2005) Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo. Journal of Immunology 174, 4924-4933.

Taylor, M.D., Harris, A., Babayan, S., Bain, O., Culshaw, A., Allen, J.E., Maizels, R.M. (2007) CTLA-4+ and CD4+CD25+ regulatory T cells inhibit protective immunity to filarial parasites in vivo. Journal of Immunology 179, 4626-4634.

Taylor, M.D., van der Werf, N., Harris, A., Graham, A.L., Bain, O., Allen, J.E., Maizels, R.M. (2009) Early recruitment of natural CD4+Foxp3+ regulatory T cells by infective larvae determines the outcome of filarial infection. European Journal of Immunology 39, 192-206.

Wilson, M.S., Taylor, M., Balic, A., Finney, C.A.M., Lamb, J.R., Maizels, R.M. (2005) Suppression of allergic airway inflammation by helminth-induced regulatory T cells. Journal of Experimental Medicine 202, 1199-1212.