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.
Taylor
Matthew D
MD
Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK. Matthew.Taylor@ed.ac.uk
van der Werf
Nienke
N
Harris
Anjanette
A
Graham
Andrea L
AL
Bain
Odile
O
Allen
Judith E
JE
Maizels
Rick M
RM
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D005368:Filariasis / Q000276:immunology* / Q000469:parasitology; D005370:Filarioidea / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology; D007814:Larva / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015704:CD4 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse