title: Alloreactive CD4 T cell activation in vivo: an autonomous function of the indirect pathway of alloantigen presentation.
abstract: Activation of alloreactive CD4 T cells occurs via the direct and indirect pathways of alloantigen presentation. A novel TCR/alloantigen transgenic system was designed that permitted in vivo visualization of CD4 T cell priming through these pathways. When both pathways of alloantigen presentation were intact, CD4 T cell activation in response to cardiac allografts was rapid and systemic by day 4 after transplantation, in contrast to that seen in response to skin allografts, which was delayed until 10-12 days after transplantation. Despite this systemic CD4 T cell activation in response to cardiac allografts, there was a paucity of activated graft-infiltrating CD4 T cells at 4 days posttransplantation. This finding suggests that the initial priming of alloimmune CD4 T cell responses occurs within draining lymphoid organs. Furthermore, alloantigens derived from cardiac allografts failed to promote thymic negative selection of developing thymocytes expressing the alloreactive TCR clonotype. In the absence of a functional direct pathway, the kinetics of activation, anatomic localization, and effector function of alloreactive CD4 T cells remained unchanged. Overall, the present study defines the anatomic and temporal characteristics of CD4 T cell alloimmune responses and demonstrates that CD4 T cell priming via the indirect pathway proceeds optimally in the absence of the direct pathway of alloantigen presentation.
authors.affiliation: Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Reed
authors.forename: Hooman
authors.initials: H
authors.lastname: Noorchashm
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Rostami
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Zarrabi
authors.forename: Alison R
authors.initials: AR
authors.lastname: Perate
authors.forename: Arjun N
authors.initials: AN
authors.lastname: Jeganathan
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Caton
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D016027:Heart Transplantation / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000096:biosynthesis / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D000949:Histocompatibility Antigens Class II; D007519:Isoantigens