Preferential Priming of Alloreactive T Cells with Indirect Reactivity

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. The indirect pathway is disproportionately activated relative to the direct pathway of T cell allorecognition, allowing the less frequent indirect pathway to play a major role in acute rejection. See editorial by Benichou and Thomson page 655.