Depletion of T regulatory cells promotes natural killer cell-mediated cardiac allograft vasculopathy.

Background. A role for natural killer (NK) cells in cardiac allograft vasculopathy (CAV) was suggested by our earlier observation that CAV arises even in the absence of detectable antidonor T-cell or B-cell reactivity in parental to F1 mouse heart grafts. However, prevention of CAV in this setting required the depletion of both NK and CD4(+) T cells. Methods. To clarify the interrelationship between NK and CD4(+) cells, we analyzed early events and selective depletion of T regulatory cells (Tregs). Hearts from C57BL/6 (B6) donors were transplanted heterotopically into BALB/c x C57BL/6 (CB6F1) recipients and NK cells, CD4(+) T cells, and Tregs were depleted with anti-NK1.1 (PK136), anti-CD4 (GK1.5), or anti-CD25 (PC61), respectively. Results. In contrast to prior studies in which the prevention of CAV at 8 weeks required the codepletion of NK and CD4(+) T cells, NK cells depletion alone eliminated CAV at 3 weeks. Furthermore, depletion of CD25(+) cells accelerated the onset and maturation of CAV at both 2 and 3 weeks (P<0.02 and P<0.001, respectively). However, anti-NK1.1 treatment prevented lesions in CD25-depleted recipients. Finally, CD4(+) T cell depletion alone did not prevent or accelerate development of CAV but inhibited the effect of CD25(+) T cell depletion. Conclusion. These data suggest that NK cells can play an important role in the early pathogenesis of CAV but that their ability to mediate early CAV can be modulated by Tregs.