Early recruitment of natural CD4+Foxp3+ Treg cells by infective larvae determines the outcome of filarial infection

Human helminth infections are synonymous with impaired immune responsiveness indicating suppression of host immunity. Using a permissive murine model of filariasis, Litomosoides sigmodontis infection of inbred mice, we demonstrate rapid recruitment and increased in vivo proliferation of CD4⁺Foxp3⁺ Treg cells upon exposure to infective L3 larvae. Within 7 days post‐infection this resulted in an increased percentage of CD4⁺T cells at the infection site expressing Foxp3. Antibody‐mediated depletion of CD25⁺ cells prior to infection to remove pre‐existing ‘natural’ CD4⁺CD25⁺Foxp3⁺ Treg cells, while not affecting initial larval establishment, significantly reduced the number of adult parasites recovered 60 days post‐infection. Anti‐CD25 pre‐treatment also impaired the fecundity of the surviving female parasites, which had reduced numbers of healthy eggs and microfilaria within their uteri, translating to a reduced level of blood microfilaraemia. Enhanced parasite killing was associated with augmented in vitro production of antigen‐specific IL‐4, IL‐5, IL‐13 and IL‐10. Thus, upon infection filarial larvae rapidly provoke a CD4⁺Foxp3⁺ Treg‐cell response, biasing the initial CD4⁺ T‐cell response towards a regulatory phenotype. These CD4⁺Foxp3⁺ Treg cells are predominantly recruited from the ‘natural’ regulatory pool and act to inhibit protective immunity over the full course of infection.