title: Preferential priming of alloreactive T cells with indirect reactivity.
abstract: The relative contributions of the direct and indirect pathways in alloimmune responses have not been fully elucidated. We report a novel murine TCR transgenic system that can simultaneously track the CD4-direct (CD4-d), CD4-indirect (CD4-i) and CD8-direct (CD8-d) pathways after transplantation. Using this system, we have observed a profoundly greater proliferation of CD4-i T cells relative to CD4-d and CD8-d T cells after transplantation. Furthermore, a much larger proportion of CD4-i T cells attain an effector phenotype. We also analyzed endogenous, wild-type T cells using enzyme-linked immunospot analysis. In naïve mice, T cells with indirect reactivity were undetectable, but T cells with direct reactivity were abundant. However, 10 days after skin or heterotopic heart transplantation, CD4-i T cells comprised approximately 10% of the CD4+ response. Consistent with increased priming of the CD4-i pathway, we observed that the CD4-i T cells were further enriched in the effector cells migrating to the allograft and in memory-like T cells persisting after rejection. Thus, priming of the CD4-i pathway is favored after transplantation, allowing a rare population to rapidly become a major component of the CD4+ T-cell response in acute allograft rejection. The generalizability of this observation to other models remains to be determined.
authors.affiliation: Department of Surgery, Division of Transplantation, University of California, San Francisco, CA, USA.
authors.forename: T V
authors.initials: TV
authors.lastname: Brennan
authors.forename: A
authors.initials: A
authors.lastname: Jaigirdar
authors.forename: V
authors.initials: V
authors.lastname: Hoang
authors.forename: T
authors.initials: T
authors.lastname: Hayden
authors.forename: F-C
authors.initials: FC
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Zaid
authors.forename: C K
authors.initials: CK
authors.lastname: Chang
authors.forename: R P
authors.initials: RP
authors.lastname: Bucy
authors.forename: Q
authors.initials: Q
authors.lastname: Tang
authors.forename: S-M
authors.initials: SM
authors.lastname: Kang