title: Impaired thymic selection and abnormal antigen-specific T cell responses in Foxn1(Δ/Δ) mutant mice.
abstract: BACKGROUND
  Foxn1(Δ/Δ) mutant mice have a specific defect in thymic development, characterized by a block in TEC differentiation at an intermediate progenitor stage, and blocks in thymocyte development at both the DN1 and DP cell stages, resulting in the production of abnormally functioning T cells that develop from an atypical progenitor population. In the current study, we tested the effects of these defects on thymic selection.
  
  
  RESULTS
  We used Foxn1(Δ/Δ); DO11 Tg and Foxn1(Δ/Δ); OT1 Tg mice as positive selection and Foxn1(Δ/Δ); MHCII I-E mice as negative selection models. We also used an in vivo system of antigen-specific reactivity to test the function of peripheral T cells. Our data show that the capacity for positive and negative selection of both CD4 and CD8 SP thymocytes was reduced in Foxn1(Δ/Δ) mutants compared to Foxn1(+/Δ) control mice. These defects were associated with reduction of both MHC Class I and Class II expression, although the resulting peripheral T cells have a broad TCR Vβ repertoire. In this deficient thymic environment, immature CD4 and CD8 SP thymocytes emigrate from the thymus into the periphery. These T cells had an incompletely activated profile under stimulation of the TCR signal in vitro, and were either hypersensitive or hyporesponsive to antigen-specific stimulation in vivo. These cell-autonomous defects were compounded by the hypocellular peripheral environment caused by low thymic output.
  
  
  CONCLUSIONS
  These data show that a primary defect in the thymic microenvironment can cause both direct defects in selection which can in turn cause indirect effects on the periphery, exacerbating functional defects in T cells.
authors.affiliation: Department of Genetics, Coverdell Center, University of Georgia, Athens, Georgia, United States of America. shiyun@uga.edu
authors.forename: Shiyun
authors.initials: S
authors.lastname: Xiao
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Manley
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D000941:Antigens; D051858:Forkhead Transcription Factors; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D016693:Receptors, Antigen, T-Cell, alpha-beta; C090140:Whn protein; D010047:Ovalbumin