CD4+ TCR repertoire heterogeneity in Schistosoma mansoni-induced granulomas.
The hallmark of Schistosoma mansoni infection is the formation of liver granulomas around deposited ova. The initiation of granuloma formation is T cell-dependent since granulomas are not formed in their absence. We investigated whether a few T cells arrive to initiate the inflammatory lesion and subsequently expand locally, or whether a large repertoire of systemically activated T cells home to the delayed type hypersensitivity reaction induced by the ova. The TCR repertoire of single granulomas from the same liver were analyzed by PCR using Vbeta-specific primers and CDR3 analysis. Each granuloma has a very diverse TCR repertoire indicating that most of the T cells recruited to these lesions are activated systemically. At the same time, sequence analysis of individually sized CDR3 products from single granuloma indicate that a fraction of T cells expand locally at the lesion site. Using TCR transgenic mice containing a pigeon cytochrome c-specific T cell population or lymphocytic choriomeningitis virus infection tracked with lymphocytic choriomeningitis virus-specific tetramers, we demonstrated that nonspecific T cells home to the granuloma if they are activated. However, recombinase-activating gene 2(-/-) pigeon cytochrome c-specific TCR transgenic mice fail to form granulomas in response to S. mansoni ova even after T cell activation, suggesting a requirement for egg-specific T cells in the initiation of these inflammatory lesions. Understanding the mechanism of T cell recruitment into granulomas has important implications for the rational design of immunotherapies for granulomatous diseases.
Hogan
Laura H
LH
Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Madison 53706, USA. lhhogan@facstaff.wisc.edu
Wang
Margaret
M
Suresh
M
M
Co
Dominic O
DO
Weinstock
Joel V
JV
Sandor
Matyas
M
D000818:Animals; D000947:Antigens, Helminth; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D022801:Complementarity Determining Regions; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D019672:Genes, T-Cell Receptor; D006099:Granuloma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012550:Schistosoma mansoni / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology
D000947:Antigens, Helminth; D022801:Complementarity Determining Regions; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D004247:DNA