title: Contributions of direct and indirect T cell alloreactivity during allograft rejection in mice.
abstract: The immune response to transplanted allogeneic tissues is mediated by T cells that recognize donor histocompatibility Ags either via direct (donor MHC and peptides) or indirect (recipient MHC and donor-derived peptides) allorecognition pathways. The relative contribution of each of these pathways to allograft rejection remains largely unknown. To address this, we used an enzyme-linked immunospot assay to define the frequency and cytokine phenotype of T cells responding via direct and indirect pathways to alloantigens at various time points following placement of allogeneic B10.A skin grafts on BALB/c recipient mice. During acute graft rejection >90% of the anti-B10.A T cell repertoire was directed toward intact donor MHC molecules, while T cells recognizing indirectly presented, donor-derived peptides accounted for <10%. This indirect response was comprised of reactivity toward both MHC-derived and, to a lesser extent, minor Ag-derived determinants. The direct and indirect alloresponses were predominantly detected in recipient lymph nodes and were mediated by T cells displaying a mixed type 1/type 2 cytokine phenotype. Six weeks following rejection, however, the memory allospecific T cell response became predominant in the recipient spleen, with only minimal activity detectable in the draining lymph nodes. This work provides a new approach for analysis of the immunophysiology of allograft rejection and should be useful for monitoring immune responses to graft Ags in human transplant recipients.
authors.affiliation: Department of Surgery, University of California, San Francisco 94114, USA.
authors.forename: G
authors.initials: G
authors.lastname: Benichou
authors.forename: A
authors.initials: A
authors.lastname: Valujskikh
authors.forename: P S
authors.initials: PS
authors.lastname: Heeger
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007519:Isoantigens / Q000235:genetics / Q000276:immunology*; D007700:Kinetics; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008912:Minor Histocompatibility Loci / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D007519:Isoantigens; D015847:Interleukin-4; D007371:Interferon-gamma