CCR2-dependent intraepithelial lymphocytes mediate inflammatory gut pathology during Toxoplasma gondii infection.
Mice of the C57BL/6 strain develop acute ileal inflammation after infection with the protozoan parasite Toxoplasma gondii. This pathology resembles many key features of human Crohn's disease, including a Th1 cytokine profile with high levels of interferon gamma (IFN-gamma), interleukin 12 (IL)-12, and tumor necrosis factor alpha (TNF)-alpha, presence of pathogenic CD4(+) T cells, and infiltration of gut flora into inflammed tissue. Using CCR2(-/-) mice, we identify a role for this chemokine receptor in the pathogenesis of inflammatory pathology during T. gondii infection. Lack of chemokine (C-C motif) receptor 2 (CCR2) was associated with low levels of CD103(+) T lymphocytes in the intraepithelial compartment, Peyer's patch, and lamina propria relative to wild-type animals. Adoptive transfer of wild-type, but not IFN-gamma(-/-), intraepithelial T lymphocytes converted CCR2 knockout mice from a resistant to susceptible phenotype with respect to parasite-triggered inflammatory gut pathology. These results for the first time show a role for intraepithelial T lymphocytes in pathogenesis of ileitis triggered by a microbial pathogen.
Egan
C E
CE
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA. cee22@cornell.edu
Craven
M D
MD
Leng
J
J
Mack
M
M
Simpson
K W
KW
Denkers
E Y
EY
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D039521:CD11c Antigen / Q000276:immunology; D007079:Ileitis / Q000276:immunology* / Q000469:parasitology; D018928:Immunity, Mucosal / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D039001:Integrin alpha Chains / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000469:parasitology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054390:Receptors, CCR2 / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014123:Toxoplasmosis / Q000276:immunology*
D015703:Antigens, CD; D039521:CD11c Antigen; C515335:Ccr2 protein, mouse; D039001:Integrin alpha Chains; D054390:Receptors, CCR2; C091367:alpha E integrins