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.